Combination therapy for treating or managing acute myelocytic leukemia

ABSTRACT

The present invention relates to methods and compositions designed for the treatment, management or prevention of cancer. The methods of the invention comprise the administration of an effective amount of one or more inhibitors of JNK in combination with the administration of an effective amount of one or more other agents useful for cancer therapy. The invention also provides pharmaceutical compositions comprising one or more inhibitors of JNK in combination with one or more other agents useful for cancer therapy. In particular, the invention is directed to methods of treatment and prevention of cancer by the administration of an effective amount of one or more inhibitors of JNK in combination with standard and experimental chemotherapies, hormonal therapies, bone marrow transplants, stem cell replacement therapies, biological therapies/immunotherapies and/or radiation therapies for treatment or prevention of cancer. Also included are methods of treatment of cancer by the administration of one or more inhibitors of JNK in combination with surgery, alone or in further combination with standard and experimental chemotherapies, hormonal therapies, bone marrow transplants, stem cell replacement therapies, biological therapies/immunotherapies and/or radiation therapies.

This application is a continuation of U.S. application Ser. No.10/384,440, filed Mar. 7, 2003, which claims the benefit of U.S.provisional application 60/362,705, filed Mar. 8, 2002, the disclosuresof which are incorporated by reference herein in their entireties.

1. FIELD OF THE INVENTION

The invention relates to combination therapies for the treatment,prevention or management of a disease or disorder in cancer patients orpatients having other proliferative diseases or disorders.

2. BACKGROUND OF THE INVENTION

Jun N-Terminal Kinase (JNK)

The Jun N-terminal kinase (JNK) pathway is activated by exposure ofcells to environmental stress or by treatment of cells withpro-inflammatory cytokines and growth factors. Targets of the JNKpathway include the transcription factors c-jun and ATF2 (Whitmarsh A.J., and Davis R. J. J Mol. Med. 74:589-607, 1996). These transcriptionfactors are members of the basic leucine zipper (bZIP) group that bindas homo- and hetero-dimeric complexes to AP1 and AP-1-like sites in thepromoters of many genes (Karin M., Liu Z. G. and Zandi E. Curr Opin CellBiol 9:240-246, 1997). JNK binds to the N-terminal region of c-jun andATF-2 and phosphorylates two sites within the activation domain of eachtranscription factor (Hibi M., Lin A., Smeal T., Minden A., Karin M.Genes Dev. 7:2135-2148, 1993; Mohit A. A., Martin M. H., and Miller C.A. Neuron 14:67-78, 1995). Three JNK enzymes have been identified asproducts of distinct genes (Hibi et al, supra; Mohit et al., supra). Tendifferent isoforms of JNK have been identified. These representalternatively spliced forms of three different genes: JNK1, JNK2, andJNK3. JNK1 and 2 are ubiquitously expressed in human tissues, whereasJNK3 is selectively expressed in the brain, heart, and testis (Dong, C.,Yang, D., Wysk, M., Whitmarsh, A., Davis, R., Flavell, R. Science270:1-4, 1998). Gene transcripts are alternatively spliced to producefour-JNK1 isoforms, four-JNK2 isoforms, and two-JNK3 isoforms. JNK1 and2 are expressed widely in mammalian tissues, whereas JNK3 is expressedalmost exclusively in the brain. Selectivity of JNK signaling isachieved via specific interactions of JNK pathway components and by useof scaffold proteins that selectively bind multiple components of thesignaling cascade. JIP-1 (JNK-interacting protein-1) selectively bindsthe MAPK module, MLK JNKK1 JNK. It has no binding affinity for a varietyof other MAPK cascade enzymes. Different scaffold proteins are likely toexist for other MAPK signaling cascades to preserve substratespecificity.

JNKs are activated by dual phosphorylation on Thr-183 and Tyr-185. JNKK1(also known as MKK 4) and JNKK2 (MKK7), two MAPKK level enzymes, canmediate JNK activation in cells (Lin A., Minden A., Martinetto H.,Claret F.-Z., Lange-Carter C., Mercurio F., Johnson G. L., and Karin M.Science 268:286-289, 1995; Tournier C., Whitmarsh A. J., Cavanagh J.,Barrett T., and Davis R. J. Proc. Nat. Acad. Sci. USA 94:7337-7342,1997). JNKK2 specifically phosphorylates JNK, whereas JNKK1 can alsophosphorylate and activate p38. Both JNKK1 and JNKK2 are widelyexpressed in mammalian tissues. JNKK1 and JNKK2 are activated by theMAPKKK enzymes, MEKK1 and 2 (Lange-Carter C. A., Pleiman C. M., GardnerA. M., Blumer K. J., and Johnson G. L., Science, 260:315-319, 1993; YanM., Dai J. C., Deak J. C., Kyriakis J. M., Zon L. I., Woodgett J. R.,and Templeton D. J., Nature, 372:798-781, 1994). Both MEKK1and MEKK2 arewidely expressed in mammalian tissues.

Activation of the JNK pathway has been documented in a number of diseasesettings, providing the rationale for targeting this pathway for drugdiscovery. In addition, molecular genetic approaches have validated thepathogenic role of this pathway in several diseases. For example,autoimmune and inflammatory diseases arise from the over-activation ofthe immune system. Activated immune cells express many genes encodinginflammatory molecules, including cytokines, growth factors, cellsurface receptors, cell adhesion molecules, and degradative enzymes.Many of these genes are regulated by the JNK pathway, through activationof the transcription factors AP-b 1 and ATF-2, including TNF-alpha,IL-2, E-selectin, and matrix metalloproteinases such as collagenase-1(Manning A. M. and Mercurio F., Exp Opin Invest Drugs, 6: 555-567,1997). Monocytes, tissue macrophages, and tissue mast cells are keysources of TNF-alpha production. The JNK pathway regulates TNF-alphaproduction in bacterial lipopolysaccharide-stimulated macrophages, andin mast cells stimulated through the FceRII receptor (Swantek J. L.,Cobb M. H., Geppert T. D., Mol. Cell. Biol., 17:6274-6282, 1997;Ishizuka, T., Tereda N., Gerwins, P., Hamelmann E., Oshiba A., Fanger G.R., Johnson G. L., and Gelfiand E. W., Proc. Nat. Acad. Sci. USA,94:6358-6363, 1997). Inhibition of JNK activation effectively modulatesTNF-alpha secretion from these cells. The JNK pathway thereforeregulates production of this key pro-inflammatory cytokine. It isbelieved that JNK is pro-apoptotic under stress or inflammatoryconditions such as exposure to UV-radiation. (Leppa and Bohman, Oncogene18:6158-6162 (1999)). Matrix metalloproteinases (MMPs) promote cartilageand bone erosion in rheumatoid arthritis, and generalized tissuedestruction in other autoimmune diseases. Inducible expression of MMPs,including MMP-3 and MMP-9, type II and IV collagenases, are regulatedvia activation of the JNK pathway and AP-1 (Gum, R., Wang, H., Lengyel,E., Juarez, J., and Boyd, D., Oncogene, 14:1481-1493, 1997). In humanrheumatoid synoviocytes activated with TNF-alpha, IL-1, or Fas ligandthe JNK pathway is activated (Han Z., Boyle D. L., Aupperle K. R.,Bennett B., Manning A. M., Firestein G. S., J. Pharm. Exp. Therap.,291:1-7, 1999; Okamoto K., Fujisawa K., Hasunuma T., Kobata T., SumidaT., and Nishioka K., Arth & Rheum, 40: 919, 1997). Inhibition of JNKactivation results in decreased AP-1 activation and collagenase-1expression (Han et al., supra). The JNK pathway therefore regulates MMPexpression in cells involved in rheumatoid arthritis.

Role of JNK in Cancer and Stroke

Cancer is characterized by uncontrolled growth, proliferation andmigration of cells. Cancer is the second leading cause of death with500,000 deaths and an estimated 1.3 million new cases in the UnitedStates in 1996. The role of signal transduction pathways contributing tocell transformation and cancer is a generally accepted concept. The JNKpathway leading to AP-1 appears to play a critical role in cancer.Expression of c-jun is altered in early lung cancer and may mediategrowth factor signaling in non-small cell lung cancer (Yin T., SandhuG., Wolfgang C. D., Burrier A., Webb R. L., Rigel D. F. Hai T., andWhelan J., J. Biol. Chem. 272:19943-19950, 1997). Indeed,over-expression of c-jun in cells results in transformation, andblocking c-jun activity inhibits MCF-7 colony formation (Szabo E., RiffeM., Steinberg S. M., Birrer M. J., Linnnoila R. I., Cancer Res.56:305-315, 1996). DNA-damaging agents, ionizing radiation, and tumornecrosis factor activate the JNK pathway. In addition to regulatingc-jun production and activity, JNK activation can regulatephosphorylation of p53 and, thus, can modulate cell cycle progression(Chen T. K., Smith L. M., Gebhardt D. K., Birrer M. J., Brown P. H.,Mol. Carcinogenesis, 15:215-226, 1996). The oncogene BCR-Ab1, associatedwith t(9,22) Philadelphia chromosome translocation of chronicmyelogenous leukemia, activates JNK and leads to transformation ofhematopoietic cells (Milne D. M., Campbell L. E., Campbell D. G., MeekD. W., J. Biol. Chem. 270:5511-5518, 1995). Selective inhibition of JNKactivation by a naturally occurring JNK inhibitory protein, calledJIP-1, blocks cellular transformation caused by BCR-Ab1 expression(Raitano A. B., Halpern J. R., Hambuch T. M., Sawyers C. L., Proc. Nat.Acad. Sci USA, 92:11746-11750, 1995). Thus, JNK inhibitors may blocktransformation and tumor cell growth.

JNK is also believed to partly responsible for cancer and/or tumorresistance to certain chemotherapeutics. The number one cause of cancersrefractory against traditional chemo drugs is the upregulation of themdrl gene. The mdr1/p-glycoprotein gene has an AP-1 binding site in itspromoter and is believed to be stimulated by JNK. Upregulation of JNKactivity has also been found in tamoxifen-resistant tumors. DN-Juninhibits tumor growth in tamoxifen-resistant animals and delaysdevelopment of tamoxifen-resistant phenotype (Daschner, et al. BreastCancer Res. 53:229, 1999; Schiff, et al. J. Natl. Cancer Inst. 92:1926,2000).

Stroke is the 3^(rd) leading cause of death and a leading cause ofdisability in the U.S. Stroke, along with neurodegenerative diseases,such as Alzheimer's (AD) and Parkinson's disease (PD) impose a hugeburden on the health care industry by impacting the quality of life ofthose affected. Loss of neuronal cell populations in stroke, AD, or PDunderlies the motor and/or cognitive deficiencies in these patientpopulations. The mechanism by which neurons die in response to insulthas not been fully elucidated; however, activation of the JNK pathwayhas been implicated as a major signaling pathway for neuronal apoptosis.(For review see Mielke K. and Herdegen T. Prog. Neurobiol. 61:45-60,2000). There have been a number of conflicting reports as to the role ofJNK activity in the regulation of apoptosis. Some studies suggest thatactivating JNK activity induces phosphorylation of C-Jun protein andprotects cells from apoptosis (Potapova, O., Basu, S., Mercola, D.,Holbrook, N., J. Biol. Chem. 276:28546-28553, 2001). However, bothpro-survival and pro-apoptotic roles of activated JNK activity have alsobeen described (Kolbus, A., Herr, I., Schreiber, M., Piu, F., Beeche,M., Wagner, E. F., Karin, M., 103:897-907, 2000; Wisdom, R., Johnson, R.S., Moore, C., EMBO J., 18:1888-197, 1999). A variety of insults havebeen shown to activate the JNK pathway in neurons. For example,activation of JNKs and phosphorylation of c-jun has been shown in brainsof rats subjected to axotomy or ischemia with reperfusion, whereneuronal cell loss was observed (Herdegen T., Claret F.-X., Kallunki,T., Matin-Villalba A., Winter C., Hunter T. and Karin M. J. Neurosci.18:5124-5135, 1998). Further, inhibition of the mixed lineage kinase(MLK)-3, an upstream kinase in the JNK pathway, by CEP-1347 preventedmotor neuron cell death following growth factor withdrawal in vitro(Maroney A. C., Glicksman M. A., Basma A. N., Walton K. M., Knight Jr.E., Murphy C. A., Bartlett B. A., Finn J. P., Angeles T., Matsuda Y.,Neff N. T. and Dionne C. A., J. Neurosci. 18:104-111, 1998), protectedcholinergic neurons following excitotoxic injury of the nucleus basalismagnocellularis (Saporito M. S., Brown, E. R., Miller M. S., MurakataC., Neff N. H., Vaught J. L., and Carswell S. Neuroscience 86:461-472,1998), and blocked the degeneration of midbrain dopamine neurons in micetreated with the neurotoxin, 1-methyl-4-phenyl tetrahydropyridine(Saporito M. S., Brown E. M., Miller M. S. and Carswell S. J. Pharm.Exp. Ther., 1999). While JNK1 and JNK2 enzymes have a widespread tissuedistribution, JNK3 is selectively expressed in brain and to a lesserextent in the heart and testis (Dong C., Yang D., Wysk M., Whitmarsh A.,Davis R., and Flavell R. Science 270:1-4, 1998). Because of thisrestricted distribution, JNK3 may be the prevailing kinase mediatingneuronal apoptosis. In support of JNK3's involvement in neuronalapoptosis, disruption of the gene encoding JNK3 in mice confersresistance to kainic acid—induced seizures and subsequent hippocampalneuronal cell death (Yang D. D., Kuan C.-Y., Whitmarsh A. J., Rincon M.,Zheng T. S., Davis R. J., Rakic P. and Flavell R. A. Nature 389:865-870,1997). Mounting evidence points to a role for the JNK pathway inneuronal apoptosis. Therefore, selective JNK inhibitors should preventneuronal cell death observed in disorders and diseases of the CNS.

Cancer Therapy

Currently, cancer therapy may involve surgery, chemotherapy, hormonaltherapy and/or radiation treatment to eradicate neoplastic cells in apatient (see, for example, Stockdale, 1998, “Principles of CancerPatient Management”, in Scientific American: Medicine, vol. 3,Rubenstein and Federman, eds., Chapter 12, Section IV). Recently, cancertherapy could also involve biological therapy or immunotherapy. All ofthese approaches pose significant drawbacks for the patient. Surgery,for example, may be contraindicated due to the health of the patient ormay be unacceptable to the patient. Additionally, surgery may notcompletely remove the neoplastic tissue. Radiation therapy is onlyeffective when the neoplastic tissue exhibits a higher sensitivity toradiation than normal tissue, and radiation therapy can also oftenelicit serious side effects. Hormonal therapy is rarely given as asingle agent and although can be effective, is often used to prevent ordelay recurrence of cancer after other treatments have removed themajority of the cancer cells. Biological therapies/immunotherapies arelimited in number and may produce side effects such as rashes orswellings, flu-like symptoms, including fever, chills and fatigue,digestive tract problems or allergic reactions.

With respect to chemotherapy, there are a variety of chemotherapeuticagents available for treatment of cancer. A significant majority ofcancer chemotherapeutics act by inhibiting DNA synthesis, eitherdirectly, or indirectly by inhibiting the biosynthesis of thedeoxyribonucleotide triphosphate precursors, to prevent DNA replicationand concomitant cell division (see, for example, Gilman et al., Goodmanand Gilman's: The Pharmacological Basis of Therapeutics, Eighth Ed.(Pergamom Press, New York, 1990)). These agents, which includealkylating agents, such as nitrosourea, anti-metabolites, such asmethotrexate and hydroxyurea, and other agents, such as etoposides,campathecins, bleomycin, doxorubicin, daunorubicin, etc., although notnecessarily cell cycle specific, kill cells during S phase because oftheir effect on DNA replication. Other agents, specifically colchicineand the vinca alkaloids, such as vinblastine and vincristine, interferewith microtubule assembly resulting in mitotic arrest. Chemotherapyprotocols generally involve administration of a combination ofchemotherapeutic agents to increase the efficacy of treatment.

Despite the availability of a variety of chemotherapeutic agents,chemotherapy has many drawbacks (see, for example, Stockdale, 1998,“Principles Of Cancer Patient Management” in Scientific AmericanMedicine, vol. 3, Rubenstein and Federman, eds., ch. 12, sect. 10).Almost all chemotherapeutic agents are toxic, and chemotherapy causessignificant, and often dangerous, side effects, including severe nausea,bone marrow depression, immunosuppression, etc. Additionally, even withadministration of combinations of chemotherapeutic agents, many tumorcells are resistant or develop resistance to the chemotherapeuticagents. In fact, those cells resistant to the particularchemotherapeutic agents used in the treatment protocol often prove to beresistant to other drugs, even those agents that act by mechanismsdifferent from the mechanisms of action of the drugs used in thespecific treatment; this phenomenon is termed pleiotropic drug ormultidrug resistance. Thus, because of drug resistance, many cancersprove refractory to standard chemotherapeutic treatment protocols.

There is a significant need for alternative cancer treatments,particularly for treatment of cancer that has proved refractory tostandard cancer treatments, such as surgery, radiation therapy,chemotherapy, and hormonal therapy. Further, it is uncommon for cancerto be treated by only one method. Thus, there is a need for developmentof new therapeutic agents for the treatment of cancer and new, moreeffective, therapy combinations for the treatment of cancer.

There is also a clear need for cancer chemotherapeutics or therapeuticregimens for treating cancer patients while reducing or avoiding thetoxicities and/or side effects associated with conventional therapies.

Citations or identification of any reference in Section 2 of thisapplication is not to be construed that such reference is prior art tothe present application.

3. SUMMARY OF THE INVENTION

The present invention is based, in part, on the recognition thatinhibitors of JNK potentiate and synergize with, enhance theeffectiveness of, improve the tolerance of, and/or reduce side effectscaused by, other cancer therapies, including conventional andexperimental chemotherapies, hormonal therapies, bone marrowtransplants, stem cell replacement therapies, biologicaltherapies/immunotherapies and radiation therapies. Thus, the inventionencompasses treatment regimens or protocols that provide bettertherapeutic profiles than current single agent therapies or currentcombination therapy regimens. Encompassed by the invention arecombination therapies that have additive potency or an additivetherapeutic effect. The invention also encompasses synergisticcombinations where the therapeutic efficacy is greater than additive.Preferably, such combinations also reduce or avoid unwanted or adverseeffects. In certain embodiments, the combination therapies encompassedby the invention provide an improved overall therapy relative toadministration of either a JNK inhibitor or any other cancer therapyalone. Given the invention, in certain embodiments, doses of existing orexperimental cancer therapies can be reduced or administered lessfrequently which increases patient compliance, improves therapy andreduces unwanted or adverse effects.

In one embodiment, the inhibitor of JNK is a small organic moleculecapable of directly inhibiting JNK activity. In another embodiment, theinhibitor of JNK is an antibody or a fragment thereof thatimmunospecifically binds to JNK or another component of the JNK pathwaythus inhibiting JNK activity.

Accordingly, the present invention relates to pharmaceuticalcompositions and prophylactic and therapeutic regimens designed toprevent, treat, or manage cancer in a patient comprising administeringone or more inhibitors of JNK in combination with one or more othercancer therapies other than the administration of a JNK inhibitor. Inparticular, the present invention provides methods of preventing,treating, or managing cancer in a patient comprising administering tosaid patient a therapeutically or prophylactically effective of one ormore inhibitors of JNK in combination with the administration of atherapeutically or prophylactically effective amount of one or morechemotherapies, hormonal therapies, bone marrow transplants, stem cellreplacement therapies, biological therapies/immunotherapies and/orradiation therapies other than the administration of a JNK inhibitor. Itis also contemplated that such methods can include the administration ofone or more JNK inhibitors in combination with surgery, alone or incombination with the administration of one or more chemotherapies,hormonal therapies, bone marrow transplants, stem cell replacementtherapies, biological therapies/immunotherapies and/or radiationtherapies other than the administration of a JNK inhibitor. In certainembodiments, the administration of inhibitors of JNK and the othercancer therapies is a therapeutic or prophylactic regimen or protocol.Such methods and regimens can encompass concurrent, sequential,synchronized or alternating/cyclic administration of the inhibitors ofJNK with one or more other cancer therapies.

The present invention is directed to methods of treating or preventingcancer by administering an effective amount of JNK inhibitor to apatient in need thereof (referred to herein as a “patient”), typically awarm-blooded animal (including a human) in combination with one or moreanti-cancer agents or radiation therapy or both. Prior toadministration, one or more compounds of this invention are typicallyformulated as a pharmaceutical composition which contains an effectivedosage amount of one or more of such compounds in combination with one(or more) pharmaceutically acceptable carrier(s). Conditions that may betreated by the compounds of this invention, or a pharmaceuticalcomposition containing the same, include cancer.

In one embodiment, the JNK inhibitor is 2H-Dibenzo(cd,g) indazol-6-One.In another embodiment, the JNK inhibitor is3-(4-fluoro-phenyl)-5-(2H-(1,2,4)triazol-3-yl)-1H-indazole. In anotherembodiment, the INK inhibitor is3-(4-(2-Piperidin-1-yl-ethoxy)-cyclohexa-1,5-dienyl)-5-(2H-(1,2,4)triazol-3-yl)-1H-indazole.

These and other aspects of this invention will be evident upon referenceto the following detailed description. To that end, certain patent andother documents are cited herein to more specifically set forth variousaspects of this invention. Each of these documents are herebyincorporated by reference herein in their entirety.

3.1 BRIEF DESCRIPTION OF THE FIGURES

FIG. 1A: FIG. 1A shows the effect of JNK inhibitor A(2H-Dibenzo(cd,g)indazol-6-One) in combination with variouschemotherapeutic agents on Lewis Lung Carcinoma (LLC) proliferation.

FIG. 1B: FIG. 1B shows the effect of JNK inhibitor B(3-(4-fluoro-phenyl)-5-(2H-(1,2,4)triazol-3-yl)-1H-indazole) incombination with various chemotherapeutic agents on tumor cellproliferation.

FIG. 2: FIG. 2 shows the JNK inhibitor B(3-(4-fluoro-phenyl)-5-(2H-(1,2,4)triazol-3-yl)-1H-indazole) incombination with cyclophosphamide, a chemotherapeutic agent on tumorgrowth.

FIG. 3: FIG. 3 shows the effect of JNK inhibitor A(2H-Dibenzo(cd,g)indazol-6-One) in combination with a chemotherapeuticagent on the apoptosis of tumor cells.

FIG. 4: FIG. 4 shows the effect of JNK inhibitor A(2H-Dibenzo(cd,g)indazol-6-One) in combination with a chemotherapeuticagent (CTX) on Lewis Lung Carcinoma proliferation.

FIG. 5: FIG. 5 shows the effect of JNK inhibitor C(3-(4-(2-Piperidin-1-yl-ethoxy)-cyclohexa-1,5-dienyl)-5-(2H-(1,2,4)triazol-3-yl)-1H-indazole)in combination with a chemotherapeutic agent (camptosar) on humancolorectal cancer cell (HCT-116) proliferation.

FIG. 6: FIG. 6 shows the structure of JNK inhibitors A, B and C.

3.2 DEFINITIONS

The terms used herein having the following meaning:

“Alkyl” means a saturated straight chain or branched non-cyclichydrocarbon having from 1 to 10 carbon atoms. Representative saturatedstraight chain alkyls include -methyl, -ethyl, -n-propyl, -n-butyl,-n-pentyl, -n-hexyl, -n-heptyl, -n-Octyl, -n-nonyl and -n-decyl; whilesaturated branched alkyls include -isopropyl, -sec-butyl, -isobutyl,-tert-butyl, -isopentyl, 2-methylbutyl, 3-methylbutyl, 2-methylpentyl,3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl,4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, 2,3-dimethylpentyl,2,4-dimethylpentyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl,2,5-dimethylhexyl, 2,2-dimethylpentyl, 2,2-dimethylhexyl,3,3-dimtheylpentyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylpentyl,3-ethylpentyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl,2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, 2-methyl-4-ethylpentyl,2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-methyl-4-ethylhexyl,2,2-diethylpentyl, 3,3-diethylhexyl, 2,2-diethylhexyl, 3,3-diethylhexyland the like.

An “alkenyl group” means a straight chain or branched non-cyclichydrocarbon having from 2 to 10 carbon atoms and including at least onecarbon-carbon double bond. Representative straight chain and branched(C₂-C₁₀)alkenyls include -vinyl, -allyl, -1-butenyl, -2-butenyl,-isobutylenyl, -1-pentenyl, -2-pentenyl, -3-methyl-1-butenyl,-2-methyl-2-butenyl, -2,3-dimethyl-2-butenyl, -1-hexenyl, -2-hexenyl,-3-hexenyl, -1-heptenyl, -2-heptenyl, -3-heptenyl, -1-Octenyl,-2-Octenyl, -3-Octenyl, -1-nonenyl, -2-nonenyl, -3-nonenyl, -1-decenyl,-2-decenyl, -3-decenyl and the like. An alkenyl group can beunsubstituted or substituted.

An “alkynyl group” means a straight chain or branched non-cyclichydrocarbon having from 2 to 10 carbon atoms and including at lease onecarbon-carbon triple bond. Representative straight chain and branched—(C₂-C₁₀)alkynyls include -acetylenyl, -propynyl, -1-butynyl,-2-butynyl, -1-pentynyl, -2-pentynyl, -3-methyl-1-butynyl, -4-pentynyl,-1-hexynyl, -2-hexynyl, -5-hexynyl, -1-heptynyl, -2-heptynyl,-6-heptynyl, -1-Octynyl, -2-Octynyl, -7-Octynyl, -1-nonynyl, -2-nonynyl,-8-nonynyl, -1-decynyl, -2-decynyl, -9-decynyl, and the like. An alkynylgroup can be unsubstituted or substituted.

“Halogen” means fluorine, chlorine, bromine or iodine.

“Keto” means a carbonyl group (i.e., C═O).

“Acyloxy means an —OC(O)alkyl group, wherein alkyl is defined above,including —OC(O)CH₃, —OC(O)CH₂CH₃, —OC(O)(CH₂)₂CH₃, —OC(O)(CH₂)₃CH₃,—OC(O)(CH₂)₄CH₃, —OC(O)(CH₂)₅CH₃, and the like.

“Alkoxy” means —O-(alkyl), wherein alkyl is defined above, including—OCH₃, —OCH₂CH₃, —O(CH₂)₂CH₃, —O(CH₂)₃CH₃, —O(CH₂)₄CH₃, —O(CH₂)₅CH₃, andthe like.

“Alkoxyalkoxy” means —O-(alkyl)-O-(alkyl), wherein each alkyl isindependently an alkyl group defined above, including —OCH₂OCH₃,—OCH₂CH₂OCH₃, —OCH₂CH₂OCH₂CH₃, and the like.

“Alkoxycarbonyl” means —C(═O)O-(alkyl), wherein alkyl is defined above,including —C(═O)O—CH₃, —C(═O)O—CH₂CH₃, —C(═O)O—(CH₂)₂CH₃,—C(═O)O—(CH₂)₃CH₃, —C(═O)O—(CH₂)₄CH₃, —C(═O)O—(CH₂)₅CH₃, and the like.

“Alkoxycarbonylalkyl” means -(alkyl)-C(═O)O-(alkyl), wherein each alkylis independently defined above, including —CH₂—C(═O)O—CH₃,—CH₂—C(═O)O—CH₂CH₃, —CH₂—C(═O)O—(CH₂)₂CH₃, —CH₂—C(═O)O—(CH₂)₃CH₃,—CH₂—C(═O)O—(CH₂)₄CH₃, —CH₂—C(═O)O—(CH₂)₅CH₃, and the like.

“Alkoxyalkyl” means -(alkyl)-O-(alkyl), wherein each alkyl isindependently an alkyl group defined above, including —CH₂OCH₃,—CH₂OCH₂CH₃, —(CH₂)₂OCH₂CH₃, —(CH₂)₂O(CH₂)₂CH₃, and the like.

“Aryl” means a carbocyclic aromatic group containing from 5 to 10 ringatoms. Representative examples include, but are not limited to, phenyl,tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, pyridinyl andnaphthyl, as well as benzo-fused carbocyclic moieties including5,6,7,8-tetrahydronaphthyl. A carbocyclic aromatic group can beunsubstituted or substituted. In one embodiment, the carbocyclicaromatic group is a phenyl group.

“Aryloxy” means —O-aryl group, wherein aryl is as defined above. Anaryloxy group can be unsubstituted or substituted. In one embodiment,the aryl ring of an aryloxy group is a phenyl group

“Arylalkyl” means -(alkyl)-(aryl), wherein alkyl and aryl are as definedabove, including —(CH₂)phenyl, —(CH₂)₂phenyl, —(CH₂)₃phenyl,—CH(phenyl)₂, —CH(phenyl)₃, —(CH₂)tolyl, —(CH₂)anthracenyl,—(CH₂)fluorenyl, —(CH₂)indenyl, —(CH₂)azulenyl, —(CH₂)pyridinyl,—(CH₂)naphthyl, and the like.

“Arylalkyloxy” means —O-(alkyl)-(aryl), wherein alkyl and aryl aredefined above, including —O—(CH₂)₂phenyl, —O—(CH₂)₃phenyl,—O—CH(phenyl)₂, —O—CH(phenyl)₃, —O—(CH₂)tolyl, —O—(CH₂)anthracenyl,—O—(CH₂)fluorenyl, —O—(CH₂)indenyl, —O—(CH₂)azulenyl, —O—(CH₂)pyridinyl,—O—(CH₂)naphthyl, and the like.

“Aryloxyalkyl” means -(alkyl)-O-(aryl), wherein alkyl and aryl aredefined above, including —CH₂—O-(phenyl), —(CH₂)₂—O-phenyl,—(CH₂)₃—O-phenyl, —(CH₂)—O-tolyl, —(CH₂)—O-anthracenyl,—(CH₂)—O-fluorenyl, —(CH₂)—O-indenyl, —(CH₂)—O-azulenyl,—(CH₂)—O-pyridinyl, —(CH₂)—O-naphthyl, and the like.

“Cycloalkyl” means a monocyclic or polycyclic saturated ring havingcarbon and hydrogen atoms and having no carbon-carbon multiple bonds.Examples of cycloalkyl groups include, but are not limited to,(C₃-C₇)cycloalkyl groups, including cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, and cycloheptyl, and saturated cyclic andbicyclic terpenes. A cycloalkyl group can be unsubstituted orsubstituted. In one embodiment, the cycloalkyl group is a monocyclicring or bicyclic ring.

“Cycloalkyloxy” means —O-(cycloalkyl), wherein cycloalkyl is definedabove, including —O-cyclopropyl, —O-cyclobutyl, —O-cyclopentyl,—O-cyclohexyl, —O-cycloheptyl and the like.

“Cycloalkylalkyloxy” means —O-(alkyl)-(cycloalkyl), wherein cycloalkyland alkyl are defined above, including —O—CH₂-cyclopropyl,—O—(CH₂)₂-cyclopropyl, —O—(CH₂)₃—-cyclopropyl, —O—(CH₂)₄-cyclopropyl,O—CH₂-cyclobutyl, O—CH₂-cyclopentyl, O—CH₂-cyclohexyl,—O—CH₂-cycloheptyl, and the like.

“Aminoalkoxy” means —O-(alkyl)-NH₂, wherein alkyl is defined above, suchas —O—CH₂—NH₂, —O—(CH₂)₂—NH₂, —O—(CH₂)₃—NH₂, —O—(CH₂)₄—NH₂,—O—(CH₂)₅—NH₂, and the like.

“Mono-alkylamino” means —NH(alkyl), wherein alkyl is defined above, suchas —NHCH₃, —NHCH₂CH₃, —NH(CH₂)₂CH₃, —NH(CH₂)₃CH₃, —NH(CH₂)₄CH₃,—NH(CH₂)₅CH₃, and the like.

“Di-alkylamino” means —N(alkyl)(alkyl), wherein each alkyl isindependently an alkyl group defined above, including —N(CH₃)₂,—N(CH₂CH₃)₂, —N((CH₂)₂CH₃)₂, —N(CH₃)(CH₂CH₃), and the like.

“Mono-alkylaminoalkoxy” means —O-(alkyl)-NH(alkyl), wherein each alkylis independently an alkyl group defined above, including —O—(CH₂)—NHCH₃,—O—(CH₂)—NHCH₂CH₃, —O—(CH₂)—NH(CH₂)₂CH₃, —O—(CH₂)—NH(CH₂)₃CH₃,—O—(CH₂)—NH(CH₂)₄CH₃, —O—(CH₂)—NH(CH₂)₅CH₃, —O—(CH₂)₂—NHCH₃, and thelike.

“Di-alkylaminoalkoxy” means —O-(alkyl)N(alkyl)(alkyl), wherein eachalkyl is independently an alkyl group defined above, including—O—(CH₂)—N(CH₃)₂, —O—(CH₂)—N(CH₂CH₃)₂, —O—(CH₂)—N((CH₂)₂CH₃)₂,—O—(CH₂)—N(CH₃)(CH₂CH₃), and the like.

“Arylamino” means —NH(aryl), wherein aryl is defined above, including—NH(phenyl), —NH(tolyl), —NH(anthracenyl), —NH(fluorenyl), —NH(indenyl),—NH(azulenyl), —NH(pyridinyl), —NH(naphthyl), and the like.

“Arylalkylamino” means —NH-(alkyl)-(aryl), wherein alkyl and aryl aredefined above, including —NH—CH₂-(phenyl), —NH—CH₂-(tolyl),—NH—CH₂-(anthracenyl), —NH—CH₂-(fluorenyl), —NH—CH₂-(indenyl),—NH—CH₂-(azulenyl), —NH—CH₂-(pyridinyl), —NH—CH₂-(naphthyl),—NH—(CH₂)₂-(phenyl) and the like.

“Alkylamino” means mono-alkylamino or di-alkylamino as defined above.

“Cycloalkylamino” means —NH-(cycloalkyl), wherein cycloalkyl is asdefined above, including —NH-cyclopropyl, —NH-cyclobutyl,—NH-cyclopentyl, —NH-cyclohexyl, —NH-cycloheptyl, and the like.

“Carboxyl” and “carboxy” mean —COOH.

“Cycloalkylalkylamino” means —NH-(alkyl)-(cycloalkyl), wherein alkyl andcycloalkyl are defined above, including —NH—CH₂-cyclopropyl,—NH—CH₂-cyclobutyl, —NH—CH₂-cyclopentyl, —NH—CH₂-cyclohexyl,—NH—CH₂-cycloheptyl, —NH—(CH₂)₂-cyclopropyl and the like.

“Aminoalkyl” means -(alkyl)-NH₂, wherein alkyl is defined above,including CH₂—NH₂, —(CH₂)₂—NH₂, —(CH₂)₃—NH₂, —(CH₂)₄—NH₂, —(CH₂)₅—NH₂and the like.

“Mono-alkylaminoalkyl” means -(alkyl)-NH(alkyl), wherein each alkyl isindependently an alkyl group defined above, including —CH₂—NH—CH₃,—CH₂—NHCH₂CH₃, —CH₂—NH(CH₂)₂CH₃, —CH₂—NH(CH₂)₃CH₃, —CH₂—NH(CH₂)₄CH₃,—CH₂—NH(CH₂)₅CH₃, —(CH₂)₂—NH—CH₃, and the like.

“Di-alkylaminoalkyl” means -(alkyl)-N(alkyl)(alkyl), wherein each alkylis independently an alkyl group defined above, including —CH₂—N(CH₃)₂,—CH₂—N(CH₂CH₃)₂, —CH₂—N((CH₂)₂CH₃)₂, —CH₂—N(CH₃)(CH₂CH₃),—(CH₂)₂—(CH₃)₂, and the like.

“Heteroaryl” means an aromatic heterocycle ring of 5- to 10 members andhaving at least one heteroatom selected from nitrogen, oxygen andsulfur, and containing at least 1 carbon atom, including both mono- andbicyclic ring systems. Representative heteroaryls are triazolyl,tetrazolyl, oxadiazolyl, pyridyl, furyl, benzofuranyl, thiophenyl,benzothiophenyl, quinolinyl, pyrrolyl, indolyl, oxazolyl, benzoxazolyl,imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isoxazolyl,pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl,cinnolinyl, phthalazinyl, quinazolinyl, pyrimidyl, oxetanyl, azepinyl,piperazinyl, morpholinyl, dioxanyl, thietanyl and oxazolyl.

“Heteroarylalkyl” means -(alkyl)-(heteroaryl), wherein alkyl andheteroaryl are defined above, including —CH₂-triazolyl, —CH₂-tetrazolyl,—CH₂-oxadiazolyl, —CH2-pyridyl, —CH₂-furyl, —CH₂-benzofuranyl,—CH₂-thiophenyl, —CH₂-benzothiophenyl, —CH₂-quinolinyl, —CH₂-pyrrolyl,—CH₂-indolyl, —CH₂-oxazoly, —CH₂-benzoxazolyl, —CH₂-imidazolyl,—CH₂-benzimidazolyl, —CH₂-thiazolyl, —CH₂-benzothiazolyl,—CH₂-isoxazolyl, —CH₂-pyrazolyl, —CH₂-isothiazolyl, —CH₂-pyridazinyl,—CH₂-pyrimidinyl, —CH₂-pyrazinyl, —CH₂-triazinyl, —CH₂-cinnolinyl,—CH₂-phthalazinyl, —CH₂-quinazolinyl, —CH₂-pyrimidyl, —CH₂-oxetanyl,—CH₂-azepinyl, —CH₂-piperazinyl, —CH₂-morpholinyl, —CH₂-dioxanyl,—CH₂-thietanyl, —CH₂-oxazolyl, —(CH₂)₂-triazolyl, and the like.

“Heterocycle” means a 5- to 7-membered monocyclic, or 7- to 10-memberedbicyclic, heterocyclic ring which is either saturated, unsaturated, andwhich contains from 1 to 4 heteroatoms independently selected fromnitrogen, oxygen and sulfur, and wherein the nitrogen and sulfurheteroatoms can be optionally oxidized, and the nitrogen heteroatom canbe optionally quatemized, including bicyclic rings in which any of theabove heterocycles are fused to a benzene ring. The heterocycle can beattached via any heteroatom or carbon atom. Heterocycles includeheteroaryls as defined above. Representative heterocycles includemorpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, hydantoinyl,valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl,tetrahydropyranyl, tetrahydropyridinyl, tetrahydroprimidinyl,tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydropyrimidinyl,tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.

“Heterocycle fused to phenyl” means a heterocycle, wherein heterocycleis defined as above, that is attached to a phenyl ring at two adjacentcarbon atoms of the phenyl ring.

“Heterocycloalkyl” means -(alkyl)-(heterocycle), wherein alkyl andheterocycle are defined above, including —CH₂-morpholinyl,—CH₂-pyrrolidinonyl, —CH₂-pyrrolidinyl, —CH₂-piperidinyl,—CH₂-hydantoinyl, —CH₂-valerolactamyl, —CH₂-oxiranyl, —CH₂-oxetanyl,—CH₂-tetrahydrofuranyl, —CH₂-tetrahydropyranyl,—CH₂-tetrahydropyridinyl, —CH₂-tetrahydroprimidinyl,—CH₂-tetrahydrothiophenyl, —CH₂-tetrahydrothiopyranyl,—CH₂-tetrahydropyrimidinyl, —CH₂-tetrahydrothiophenyl,—CH₂-tetrahydrothiopyranyl, and the like.

The term “substituted” as used herein means any of the above groups(i.e., aryl, arylalkyl, heterocycle and heterocycloalkyl) wherein atleast one hydrogen atom of the moiety being substituted is replaced witha substituent. In one embodiment, each carbon atom of the group beingsubstituted is substituted with no more that two substituents. Inanother embodiment, each carbon atom of the group being substituted issubstituted with no more than one substituent. In the case of a ketosubstituent, two hydrogen atoms are replaced with an oxygen which isattached to the carbon via a double bond. Substituents include halogen,hydroxyl, alkyl, haloalkyl, mono- or di-substituted aminoalkyl,alkyloxyalkyl, aryl, arylalkyl, heterocycloalkyl, —NR_(a)R_(b),—NR_(a)C(═O)R_(b), heterocycle, —NR_(a)C(═O)NR_(a)R_(b),—NR_(a)C(═O)OR_(b)—NR_(a)SO₂R_(b), —OR_(a),—(═O)R_(a)C(═O)OR_(a)—C(═O)NR_(a)R_(b), —OC(═O)R_(a), —OC(═O)OR_(a),—OC(═O)NR_(a)R_(b), —NR_(a)SO₂R_(b), or a radical of the formula—Y-Z-R_(a) where Y is alkanediyl, or a direct bond, Z is —O—, —S—,—N(R_(b))—, —(═O), —(═O)O, —OC(═O)—, —N(R_(b))C(═O)—, —C(═O)N(R_(b))— ora direct bond, wherein R_(a) and R_(b) are the same or different andindependently hydrogen, amino, alkyl, haloalkyl, aryl, arylalkyl,heterocycle, or heterocylealkyl, or wherein R_(a) and R_(b) takentogether with the nitrogen atom to which they are attached form aheterocycle.

“Haloalkyl” means alkyl, wherein alkyl is defined as above, having oneor more hydrogen atoms replaced with halogen, wherein halogen is asdefined above, including —CF₃, —CHF₂, —CH₂F, —CBr₃, —CHBr₂, —CH₂Br,—CCl₃, —CHCl₂, —CH₂Cl, —CI₃, —CHI₂, —CH₂I, —CH₂—CF₃, —CH₂—CHF₂,—CH₂—CH₂F, —CH₂—CBr₃, —CH₂—CHBr₂, —CH₂—CH₂Br, —CH₂—CCl₃, —CH₂—CHCl₂,—CH₂—CH₂CI, —CH₂—CI₃, —CH₂—CHI₂, —CH₂—CH₂I, and the like.

“Hydroxyalkyl” means alkyl, wherein alkyl is as defined above, havingone or more hydrogen atoms replaced with hydroxy, including —CH₂OH,—CH₂CH₂OH, —(CH₂)₂CH₂OH, —(CH₂)₃CH₂OH, —(CH₂)₄CH₂OH, —(CH₂)₅CH₂OH,—CH(OH)—CH₃, —CH₂CH(OH)CH₃, and the like.

“Hydroxy” means —OH.

“Sulfonyl” means —SO₃H;

“Sulfonylalkyl” means —SO₂-(alkyl), wherein alkyl is defined above,including —SO₂—CH₃, —SO₂—CH₂CH₃, —SO₂—(CH₂)₂CH₃, —SO₂—(CH₂)₃,—SO₂—(CH₂)₄CH₃, —SO₂—(CH₂)₅CH₃, and the like.

“Sulfinylalkyl” means —SO-(alkyl), wherein alkyl is defined above,including —SO—CH₃, —SO—CH₂CH₃, —SO—(CH₂)₂CH₃, —SO—(CH₂)₃CH₃,—SO—(CH₂)₄CH₃, —SO—(CH₂)₅CH₃, and the like.

“Thioalkyl” means —S-(alkyl), wherein alkyl is defined above, including—S—CH₃, —S—CH₂CH₃, —S—(CH₂)₂CH₃, —S—(CH₂)₃CH₃, —S—(CH₂)₄CH₃,—S—(CH₂)₅CH₃, and the like.

An “effective amount” when used in connection with a JNK Inhibitor is anamount of the JNK Inhibitor that is useful for treating or preventing acardiovascular or renal disease.

An “effective amount” when used in connection with another active agentis an amount of the other active agent that is useful for providing theagent's therapeutic or prophylactic effect.

As used herein, the term “pharmaceutically acceptable salt(s)” refer tosalts prepared from pharmaceutically acceptable non-toxic acids or basesincluding inorganic acids and bases and organic acids and bases.Suitable pharmaceutically acceptable base addition salts for thecompound of the present invention include, but are not limited tometallic salts made from aluminum, calcium, lithium, magnesium,potassium, sodium and zinc or organic salts made from lysine,N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine (N-methylglucamine) and procaine. Suitablenon-toxic acids include, but are not limited to, inorganic and organicacids such as acetic, alginic, anthranilic, benzenesulfonic, benzoic,camphorsulfonic, citric, ethenesulfonic, formic, fumaric, furoic,galacturonic, gluconic, glucuronic, glutamic, glycolic, hydrobromic,hydrochloric, isethionic, lactic, maleic, malic, mandelic,methanesulfonic, mucic, nitric, pamoic, pantothenic, phenylacetic,phosphoric, propionic, salicylic, stearic, succinic, sulfanilic,sulfuric, tartaric acid, and p-toluenesulfonic acid. Specific non-toxicacids include hydrochloric, hydrobromic, phosphoric, sulfuric, andmethanesulfonic acids. Examples of specific salts thus includehydrochloride and mesylate salts. Others are well-known in the art, seefor example, Remington's Pharmaceutical Sciences, 18th eds., MackPublishing, Easton Pa. (1990) or Remington: The Science and Practice ofPharmacy, 19th eds., Mack Publishing, Easton Pa. (1995).

As used herein and unless otherwise indicated, the term “prodrug” meansa a compound that can hydrolyze, oxidize, or otherwise react underbiological conditions (in vitro or in vivo) to provide a JNK Inhibitor.Examples of prodrugs include, but are not limited to, biohydrolyzableamides, biohydrolyzable esters, biohydrolyzable carbamates,biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzablephosphate analogues. In one embodiment, prodrugs are the lower alkylesters of a carboxylic acid group of a JNK Inhibitor. The carboxylateesters are conveniently formed by esterification. Prodrugs can typicallybe prepared using well-known methods, such as those described byBurger's Medicinal Chemistry and Drug Discovery 6th ed. (Donald J.Abraham ed., 2001, Wiley) and Design and Application of Prodrugs (H.Bundgaard ed., 1985, Harwood Academic Publishers Gmfh).

Various JNK Inhibitors can contain one or more chiral centers and canexist as racemic mixtures of enantiomers or mixtures of diastereomers.This invention encompasses the use of enantiomers, as well as the use ofmixtures of those forms. For example, enantiomers or racemates of a JNKInhibitor, or mixtures thereof, can be used in the methods of theInvention.

The phrase “modulation of JNK” or “by modulating JNK” means theinhibition or activation, preferably the inhibition, of a protein knownas Jun N-terminal kinase (JNK) and all isoforms thereof expressed by JNK1, JNK 2, and JNK 3 genes (Hibi M., Lin A., Smeal T., Minden A., KarinM. Genes Dev. 7:2135-2148, 1993; Mohit A. A., Martin M. H., and MillerC. A. Neuron 14:67-78, 1995; Gupta, S., Barrett, T., Whitmarsh, A. J.,Cavanagh, J., Sluss, H. K., Derijard, B. and Davis, R. J. The EMBO J.15:2760-2770, 1996). The modulation of JNK can be achieved on the mRNAlevel, protein level and kinase activity level.

“JNK” means a protein and all isoforms thereof expressed by JNK 1, JNK2, and JNK 3 genes (Gupta, S., Barrett, T., Whitmarsh, A. J., Cavanagh,J., Sluss, H. K., Derijard, B. and Davis, R. J. The EMBO J.15:2760-2770, 1996).

“JNK inhibitor” or “inhibitors of JNK” means any molecule that blocks,reduces or retards the phosphorylation of c-Jun or other substrates byJNK or reduces the amount of JNK present in the cell. Inhibition may beeither direct or indirect, preferably inhibition is direct. Inhibitorsof JNK include, but are not limited to, small organic molecules(preferable with a molecular weight of less than 1000) which are notpeptides, proteins, nucleic acids, polypeptides or oligonucleotides; orantibodies or a fragment thereof that immunospecifically binds to JNK oranother component of the JNK pathway. In certain embodiments, inhibitorsof JNK or another component of the JNK pathway, can inhibit eitherupstream or downstream. In one embodiment, JNK inhibitor means acompound capable of inhibiting the activity of JNK in vitro or in vivo.The JNK inhibitor can be in the form of a or a pharmaceuticallyacceptable salt, free base, solvate, hydrate, stereoisomer, clathrate orprodrug thereof. Such inhibitory activity can be determined by an assayor animal model well-known in the art. In one embodiment, the JNKinhibitor is a compound of structure (I)-(XX).

“JNK pathway” means any biological molecule which has a direct orindirect effect on the activity of JNK.

“Direct inhibition” means that the JNK inhibitor directly interacts withJNK.

“Indirect inhibition” means that the JNK inhibitor blocks, reduces orretards JNK activity by interacting with a component of the JNK pathwayother than JNK.

As used herein, a “therapeutically effective amount” refers to thatamount of the therapeutic agent sufficient to destroy, modify, controlor remove primary, regional or metastatic cancer tissue. Atherapeutically effective amount may refer to the amount of therapeuticagent sufficient to delay or minimize the spread of cancer. Atherapeutically effective amount may also refer to the amount of thetherapeutic agent that provides a therapeutic benefit in the treatmentor management of cancer. Further, a therapeutically effective amountwith respect to a therapeutic agent of the invention means that amountof therapeutic agent alone, or in combination with other therapies, thatprovides a therapeutic benefit in the treatment or management of cancer,including the amelioration of symptoms associated with the disease beingtreated. Used in connection with an amount of an inhibitor of JNK, theterm can encompass an amount that improves overall therapy, reduces oravoids unwanted effects, or enhances the therapeutic efficacy of orsynergizes with another therapeutic agent.

As used herein, a “prophylactically effective amount” refers to thatamount of the prophylactic agent sufficient to result in the preventionof the recurrence or spread of cancer. A prophylactically effectiveamount may refer to the amount of prophylactic agent sufficient toprevent the recurrence or spread of cancer or the occurrence of canceror metastasis in a patient, including, but not limited to, thosepredisposed to cancer or previously exposed to carcinogens. Aprophylactically effective amount may also refer to the amount of theprophylactic agent that provides a prophylactic benefit in theprevention of cancer. Further, a prophylactically effective amount withrespect to a prophylactic agent of the invention means that amount ofprophylactic agent alone, or in combination with other agents, thatprovides a prophylactic benefit in the prevention of cancer. Used inconnection with an amount of an inhibitor of JNK, the term can encompassan amount that improves overall prophylaxis or enhances the prophylacticefficacy of or synergizes with another prophylactic or therapeuticagent.

As used herein, the terms “therapies” and “therapy” can refer to anyprotocol(s), method(s) and or agent(s) that can be used in theprevention, treatment, or management of cancer. In certain embodiments,the terms “therapy” and “therapies” refer to cancer chemotherapy,radiation therapy, hormonal therapy, biological therapy, and/or othertherapies useful for the treatment of cancer known to an oncologistskilled in the art.

As used herein, a “therapeutic protocol” refers to a regimen of timingand dosing of one or more therapeutic agents.

As used herein, a “prophylactic protocol” refers to a regimen of timingand dosing of one or more prophylactic agents.

A used herein, a “protocol” includes dosing schedules and dosingregimens. The protocols herein are methods of use.

As used herein, “in combination” refers to the use of more than oneprophylactic and/or therapeutic agents against a disease or disorder.

As used herein, the phrase “non-responsive/refractory” is used todescribe patients treated with currently available cancer therapies suchas chemotherapy, radiation therapy, surgery, hormonal therapy and/orbiological therapy/immunotherapy wherein the therapy is not clinicallyadequate to treat the patients such that these patients need additionaleffective therapy, e.g., remain unsusceptible to therapy. The phrase canalso describe patients who respond to therapy yet suffer from sideeffects, relapse, develop resistance, etc. In various embodiments,“non-responsive/refractory” means that at least some significant portionof the cancer cells are not killed or their cell division arrested. Thedetermination of whether the cancer cells are“non-responsive/refractory” can be made either in vivo or in vitro byany method known in the art for assaying the effectiveness of treatmenton cancer cells, using the art-accepted meanings of “refractory” in sucha context. In various embodiments, a cancer is“non-responsive/refractory” where the number of cancer cells has notbeen significantly reduced, or has increased.

As used herein, the phrase “low tolerance” refers to a state in whichthe patient suffers from side effects from treatment so that the patientdoes not benefit from and/or will not continue therapy because of theadverse effects.

As used herein, the term “patient” means an animal (e.g., cow, horse,sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit orguinea pig), in one embodiment a mammal such as a non-primate and aprimate (e.g., monkey, baboon, chimpanzee and human), and in anotherembodiment a human. In certain embodiments, the patient is an infant,child, adolescent or adult.

As used herein, the term “adjunctive” is used interchangeably with “incombination” or “combinatorial.” Such terms are also used where two ormore therapeutic or prophylactic agents affect the treatment orprevention of the same disease.

As used herein, the term “potentiate” refers to an improvement in theefficacy of a therapeutic agent at its common or approved dose.

As used herein, the phrase “side effects” encompasses unwanted andadverse effects of a prophylactic or therapeutic agent. Adverse effectsare always unwanted, but unwanted effects are not necessarily adverse.An adverse effect from a prophylactic or therapeutic agent might beharmful or uncomfortable or risky. Side effects from chemotherapyinclude, but are not limited to, gastrointestinal toxicity such as, butnot limited to, early and late-forming diarrhea and flatulence; nausea;vomiting; anorexia; leukopenia; anemia; neutropenia; asthenia; abdominalcramping; fever; pain; loss of body weight; dehydration; alopecia;dyspnea; insomnia; dizziness, mucositis, xerostomia, and kidney or renalfailure, as well as constipation, nerve and muscle effects, temporary orpermanent damage to kidneys and bladder, flu-like symptoms, fluidretention, and temporary or permanent infertility. Side effects fromradiation therapy include but are not limited to fatigue, dry mouth, andloss of appetite. Other side effects include gastrointestinal toxicitysuch as, but not limited to, early and late-forming diarrhea andflatulence; nausea; vomiting; anorexia; leukopenia; anemia; neutropenia;asthenia; abdominal cramping; fever; pain; loss of body weight;dehydration; alopecia; dyspnea; insomnia; dizziness, mucositis,xerostomia, and kidney failure. Side effects from biologicaltherapies/immunotherapies include but are not limited to rashes orswellings at the site of administration, flu-like symptoms such asfever, chills and fatigue, digestive tract problems and allergicreactions. Side effects from hormonal therapies include but are notlimited to nausea, fertility problems, depression, loss of appetite, eyeproblems, headache, and weight fluctuation. Additional undesired effectstypically experienced by patients are numerous and known in the art.Many are described in the Physicians'Desk Reference (56^(th) ed., 2002).

As used herein, the terms “manage”, “managing” and “management” refer tothe beneficial effects that a patient derives from a prophylactic ortherapeutic agent, which does not result in a cure of the disease. Incertain embodiments, a patient is administered one or more prophylacticor therapeutic agents to “manage” a disease so as to prevent theprogression or worsening of the disease.

As used herein, the terms “prevent”, “preventing” and “prevention” referto the prevention of the recurrence, spread or onset of primary canceror metastasis in a patient resulting from the administration of aprophylactic or therapeutic agent.

As used herein, the terms “treat”, “treating” and “treatment” refer tothe eradication, removal, modification, or control of primary, regional,or metastatic cancer tissue that results from the administration of oneor more prophylactic or therapeutic agents. In certain embodiments, suchterms refer to the minimizing or delay of the spread of cancer resultingfrom the administration of one or more prophylactic or therapeuticagents to a patient with such a disease.

4. DETAILED DESCRIPTION OF THE INVENTION

As mentioned above, the present invention is directed to methods usefulfor treating, preventing or managing cancer by administering to apatient in need thereof one or more JNK inhibitors in combination withone or more anti-cancer agents and/or radiation therapy. RepresentativeJNK inhibitors of the present invention include, but are not limited to,indazoles, anilinopyrimidine, isothiazoloanthrones, isoxazoloanthrones,isoindolanthrones, pyrazoloanthrones and derivatives thereof.

In certain embodiments, inhibitors of JNK decrease the activity of JNK.In other embodiments, inhibitors of JNK decrease the amount of JNKpresent in the cell. In other embodiments, inhibitors of JNK decreasethe amount of JNK mRNA, or mRNA of another component of the JNK pathway,in the cell.

In one embodiment, the inhibitor of JNK is a small organic moleculecapable of inhibiting JNK activity or another component of the JNKpathway. In another embodiment, the inhibitor of JNK is an antibody or afragment thereof that immunospecifically binds to JNK or anothercomponent of the JNK pathway. In another embodiment, the JNK inhibitoris triplex DNA that inhibits DNA transcription or replication of JNK orof another component of the JNK pathway. In another embodiment, JNK oranother component of the JNK pathway, is inhibited through viraltherapy. In another embodiment, the inhibitor of JNK, or anothercomponent of the JNK pathway, is dominant-negative JNK (DN-JNK). Incertain embodiments, inhibitors of JNK can inhibit either upstream ordownstream of JNK.

In a preferred embodiment, the invention encompasses the use of a JNKinhibitor in combination with a chemotherapeutic agent such as anapoptosis inducing agent to treat, prevent or manage cancer. In afurther embodiment, the chemotherapeutic includes, but is not limitedto, paclitaxel, irinotecan, camptothecin, cyclophosphamide,5-fluorouracil, cisplatinum, carboplatin, methotrexate, trimetrexate,Erbitux™, thalidomide, any SelCid™ or IMiD™ compound, in particularActimid™ or Revimid™.

The present invention is based, in part, on the recognition thatinhibitors of JNK potentiate and synergize with, enhance theeffectiveness of, improve the tolerance of, and/or reduce side effectscaused by, other cancer therapies, including current standard andexperimental chemotherapies, hormonal therapies, biologicaltherapies/immunotherapies, bone marrow transplants, stem cellreplacement therapies and radiation therapies. Thus, the inventionencompasses treatment regimens or protocols that provide bettertherapeutic profiles than current single agent therapies or currentcombination therapy regimens. Encompassed by the invention arecombination therapies that have additive potency or an additivetherapeutic effect. The invention also encompasses synergisticcombinations where the therapeutic ratio is greater than additive.Preferably, such combinations also reduce or avoid unwanted or adverseeffects. In certain embodiments, the combination therapies encompassedby the invention provide an improved overall therapy relative toadministration of either an inhibitors of JNK or any other cancertherapy alone. Given the invention, in certain embodiments, doses ofexisting or experimental cancer therapies can be reduced or administeredless frequently which increases patient compliance, improves therapy andreduces unwanted or adverse effects. In one embodiment, the cancer isresistant to cancer treatment, such as chemotherapy or radiationtherapy.

Accordingly, the present invention relates to pharmaceuticalcompositions and prophylactic and therapeutic regimens designed toprevent, treat, or manage cancer in a patient comprising administeringone or more inhibitors of JNK in combination with one or more othercancer therapies other than the administration of a JNK inhibitor. Inparticular, the present invention provides methods of preventing,treating, or managing cancer in a patient comprising administering tosaid patient a therapeutically or prophylactically effective of one ormore inhibitors of JNK in combination with the administration of atherapeutically or prophylactically effective amount of one or morechemotherapies, hormonal therapies, biologicaltherapies/immunotherapies, bone marrow transplants, stem cellreplacement therapies and radiation therapies other than theadministration of a JNK inhibitor. It is also contemplated that suchmethods can include the administration of one or more JNK inhibitors incombination with surgery, alone or in combination with theadministration of one or more chemotherapies, hormonal therapies,biological therapies/immunotherapies, bone marrow transplants, stem cellreplacement therapies and radiation therapies other than theadministration of a JNK inhibitor. In certain embodiments, theadministration of inhibitors of JNK and the other cancer therapies is atherapeutic or prophylactic regimen or protocol. Such methods andregimens can encompass concurrent, sequential or alternating/cyclicadministration of the inhibitors of JNK with one or more other cancertherapies.

In one embodiment, the inhibitor of JNK is administered with anothercancer therapy that works by the same mechanism as the inhibitor of JNK.In another embodiment, an inhibitor of JNK is administered with anothercancer therapy that works by a different mechanism than the inhibitor ofJNK. By example and not by limitation, the cancer therapy can beapoptosis inducing, cytotoxic, antimitotic, anti-angiogenic, a modulatorof TNF-alpha, tubulin stabilizing, microtubule formation inhibiting,topoisomerase active, antimetabolite, or DNA interactive agents. Inother embodiments, the cancer therapy administered with an inhibitor ofJNK is gene based. In other embodiments, the therapy is another antibodythat is not an inhibitor of JNK such as Erbitux™.

In other embodiments, the invention encompasses the use of anti-cancervaccines; or antibodies that immunoreact with Ecr, the RGD-directedadhesion receptor found on the surface of both endothelial and melanomacells with one or more JNK inhibitors. Similarly, the JNK inhibitor canbe used with antibodies which are useful for inhibiting the ability ofcells that contain the adhesion receptor to adhere to a subendothelialmatrix composed of vitronectin, fibrinogen or von Willegrand factor.Accordingly, the invention encompasses the use of JNK inhibitors withagents that are useful for inhibition of angiogenesis or inhibition ofother functions including, but not limited to, cell proliferation, cellattachment, cell migration, granulation tissue development, and/orinflammation.

The methods and compositions of the invention are useful not only inuntreated patients but are also useful in the treatment of patientspartially or completely refractory to current standard and experimentalcancer therapies, including, but not limited to, chemotherapies,hormonal therapies, biological therapies/immunotherapies, bone marrowtransplants, stem cell replacement therapies and radiation therapies,and/or surgery. In one embodiment, the methods and compositions of theinvention are useful in the treatment of patients with cancer(s) whichis refractory against current chemotherapeutic agents. In anotherembodiment, the methods and compositions of the invention are useful inthe treatment of patients with cancer(s) which is refractory againstcurrent multidrug therapies. In another embodiment, the methods andcompositions of the invention are useful in the treatment of patientswith cancer(s) which is refractory against tamoxifen. In a preferredembodiment, the invention provides therapeutic and prophylactic methodsfor the treatment or prevention of cancer that has been shown to be ormay be refractory or non-responsive to therapies other than thosecomprising administration of JNK inhibitors. In another preferredembodiment, the invention provides therapeutic and prophylactic methodsfor the treatment or prevention of cancer that has been shown to be ormay be refractory or non-responsive to therapies comprisingadministration of JNK inhibitors.

Further, the methods of the invention permit the treatment of cancerusing lower and/or less frequent doses of chemotherapies, hormonaltherapies, biological therapies/immunotherapies, bone marrowtransplants, stem cell replacement therapies and radiation therapies toreduce the incidence of unwanted or adverse effects caused byadministration of current/conventional agents while maintaining orenhancing the efficacy of treatment. In other embodiments of theinvention, lower and/or less frequent doses of JNK inhibitors can beused for the treatment and/or prevention of cancer.

In certain embodiments, the invention provides prophylactic andtherapeutic regimen or protocols comprising the administration of aninhibitor of JNK in combination with one or more chemotherapies,hormonal therapies, biological therapies/immunotherapies, bone marrowtransplants, stem cell replacement therapies and radiation therapiesother than the administration of a JNK inhibitor.

It is contemplated that the methods of treatment also include surgery incombination with the administration of an inhibitor of JNK incombination with one or more chemotherapies, hormonal therapies,biological therapies/immunotherapies, bone marrow transplants, stem cellreplacement therapies and radiation therapies other than theadministration of a JNK inhibitor.

In other embodiments, the invention provides prophylactic andtherapeutic protocols comprising the administration of an inhibitor ofJNK in combination with one or more hormonal therapies alone or,optionally, in combination with chemotherapies, hormonal therapies,biological therapies/immunotherapies, bone marrow transplants, stem cellreplacement therapies and radiation therapies other than theadministration of a JNK inhibitor.

In other embodiments, the invention provides prophylactic andtherapeutic protocols comprising the administration of an inhibitor ofJNK in combination with one or more biological therapies/immunotherapiesalone or, optionally, in combination with chemotherapies, hormonaltherapies, biological therapies/immunotherapies, bone marrowtransplants, stem cell replacement therapies and radiation therapiesother than the administration of a JNK inhibitor.

In yet other embodiments, the invention provides prophylactic andtherapeutic protocols comprising the administration of a JNK inhibitorin combination with one or more radiation therapies alone or,optionally, in combination with chemotherapies, hormonal therapies, bonemarrow transplants, stem cell replacement therapies, and/or biologicaltherapies/immunotherapies other than the administration of a JNKinhibitor.

The present invention also contemplates methods of treatment comprisingthe administration of a JNK inhibitor in combination with surgery alone.

In a specific embodiment, the invention provides prophylactic andtherapeutic protocols comprising the administration of a JNK inhibitorin combination with one or more cancer chemotherapeutic agents, such asbut not limited to: doxorubicin, epirubicin, cyclophosphamide,5-fluorouracil, taxanes such as docetaxel and paclitaxel, leucovorin,levamisole, irinotecan, estramustine, etoposide, vinblastine,dacarbazine, nitrosoureas such as carmustine and lomustine, vincaalkaloids, platinum compounds, cisplatin, mitomycin, vinorelbine,gemcitabine, carboplatin, hexamethylmelamine, topotecan, Erbitux™,thalidomide, any SelCid™ or IMiD™ compounds, in particular Actimid™ andRevimid™. Such methods can optionally further comprise theadministration of other cancer therapies, such as but not limited toradiation therapy, biological therapies, hormonal therapies and/orsurgery other than the administration of a JNK inhibitor.

In another specific embodiment, the invention provides prophylactic andtherapeutic protocols comprising the administration of a JNK inhibitorin combination with one or more anti-metastatic agents, including, butnot limited to sulphated polysaccharides andsulphaminoheparosanssulphates.

In another specific embodiment, the invention provides prophylactic andtherapeutic regimens or protocols comprising the administration of a JNKinhibitor in combination with administration of one or more types ofradiation therapy, such as external-beam radiation therapy, interstitialimplantation of radioisotopes (I-125, palladium, iridium), radioisotopessuch as strontium-89, thoracic radiation therapy, intraperitoneal P-32radiation therapy, and/or total abdominal and pelvic radiation therapy.Such methods can optionally further comprise the administration of othercancer therapies, such as but not limited to chemotherapies, biologicaltherapies/immunotherapies, bone marrow transplants, stem cellreplacement therapies, hormonal therapies and/or surgery other than theadministration of a JNK inhibitor.

In yet another specific embodiment, the invention provides prophylacticand therapeutic protocols comprising the administration of a JNKinhibitor in combination with one or more biologicaltherapies/immunotherapies or hormonal therapies other than theadministration of a JNK inhibitor, such as faslodex, tamoxifen,leuprolide or other LHRH agonists, non-steroidal antiandrogens(flutamide, nilutamide, bicalutamide), steroidal antiandrogens(cyproterone acetate), anti-inflammatory steroids (dexamethasone),estrogens (DES, chlorotrianisene, ethinyl estradiol, congugatedestrogens U.S.P., DES-diphosphate), aromatase inhibitors (e.g.,Arimidex®, anastrozole, letrozole and exemestane), aminoglutethimide,hydrocortisone, flutamide, progesterone, ketoconazole, prednisone,interferon alpha, interleukin-2, tumor necrosis factor-alpha, and/ormelphalan. Such methods can optionally further comprise theadministration of other cancer therapies, such as but not limited toradiation therapy, chemotherapies, bone marrow transplants, stem cellreplacement therapies and/or surgery.

The invention provides methods of preventing, treating or managingcancer, including, but not limited to, the cancers discussed in Section4.1.1.1. Specific examples of cancers that can be treated by the methodsand compositions of the invention include, but are not limited to,cancer of the head, neck, eye, mouth, throat, esophagus, chest, bone,lung, colon, rectum, stomach, prostate, breast, ovaries, testicles orother reproductive organs, skin, thyroid, blood, lymph nodes, kidney,liver, pancreas, and brain or central nervous system. In particularembodiments, the prophylactic and/or therapeutic protocols are designedto prevent, treat or manage breast cancer. In certain embodiments, theprophylactic and/or therapeutic protocols are designed to prevent,treat, or manage colon cancer. The prophylactic and therapeutic regimensor protocols of the invention are also designed to prevent, treat, ormanage prostate cancer. In other embodiments, the prophylactic and/ortherapeutic protocols are designed to prevent, treat, or managemelanoma. In other embodiments, the prophylactic and/or therapeuticprotocols are designed to prevent, treat, or manage multiple myeloma. Inother embodiments, prophylactic and/or therapeutic protocols aredesigned to prevent, treat, or manage lung cancer. In yet otherembodiments, prophylactic and/or therapeutic protocols are designed toprevent, treat, or manage ovarian cancer.

Preferred embodiments encompassed by the invention are methods ofdelivering one or more inhibitors of JNK as adjunctive therapy incombination with existing and experimental cancer therapies;pharmaceutical compositions and formulas for administration comprisingone or more inhibitors of JNK and one or more existing cancer therapies;kits comprising said pharmaceutical compositions; and methods oftreating, preventing, and/or managing cancer using the prophylactic ortherapeutic protocols and pharmaceutical compositions of the invention.The invention also encompasses the administration of one or moreinhibitors of JNK alone to patients refractory to other cancertreatments or that do not tolerate other such treatments because ofunwanted or adverse effects.

4.1 Prophylactic/Therapeutic Methods

The present invention encompasses methods for treating, preventing, ormanaging cancer in a patient comprising administering one or moreinhibitors of JNK in combination with one or more other therapeuticagents useful in the treatment, prevention or management of cancer. Incertain embodiments, an inhibitor of JNK is administered to a mammal,preferably a human, concurrently with one or more other therapeuticagents useful for the treatment of cancer. The term “concurrently” isnot limited to the administration of prophylactic or therapeutic agentsat exactly the same time, but rather it is meant that an inhibitor ofJNK and the other agent are administered to a mammal in a sequence andwithin a time interval such that the JNK inhibitor can act together withthe other agent to provide an increased benefit than if they wereadministered otherwise. For example, each prophylactic or therapeuticagent (e.g., chemotherapy, radiation therapy, hormonal therapy orbiological therapy) may be administered at the same time or sequentiallyin any order at different points in time; however, if not administeredat the same time, they should be administered sufficiently close in timeso as to provide the desired therapeutic or prophylactic effect. Eachtherapeutic agent can be administered separately, in any appropriateform and by any suitable route. In other embodiments, the JNK inhibitoris administered before, concurrently or after surgery. Preferably thesurgery completely removes localized tumors or reduces the size of largetumors. Surgery can also be done as a preventive measure or to relievepain. In various embodiments, the prophylactic or therapeutic agents areadministered less than I hour apart, at about 1 hour apart, at about 1hour to about 2 hours apart, at about 2 hours to about 3 hours apart, atabout 3 hours to about 4 hours apart, at about 4 hours to about 5 hoursapart, at about 5 hours to about 6 hours apart, at about 6 hours toabout 7 hours apart, at about 7 hours to about 8 hours apart, at about 8hours to about 9 hours apart, at about 9 hours to about 10 hours apart,at about 10 hours to about 1 hours apart, at about 1 hours to about 12hours apart, no more than 24 hours apart or no more than 48 hours apart.In preferred embodiments, two or more components are administered withinthe same patient visit.

In other embodiments, the prophylactic or therapeutic agents areadministered at about 2 to 4 days apart, at about 4 to 6 days apart, atabout 1 week part, at about 1 to 2 weeks apart, or more than 2 weeksapart. In preferred embodiments, the prophylactic or therapeutic agentsare administered in a time frame where both agents are still active. Oneskilled in the art would be able to determine such a time frame bydetermining the half life of the administered agents.

In certain embodiments, the prophylactic or therapeutic agents of theinvention are cyclically administered to a patient. Cycling therapyinvolves the administration of a first agent for a period of time,followed by the administration of a second agent and/or third agent fora period of time and repeating this sequential administration. Cyclingtherapy can reduce the development of resistance to one or more of thetherapies, avoid or reduce the side effects of one of the therapies,and/or improves the efficacy of the treatment.

In certain embodiments, prophylactic or therapeutic agents areadministered in a cycle of less than about 3 weeks, about once every twoweeks, about once every 10 days or about once every week. One cycle cancomprise the administration of a therapeutic or prophylactic agent byinfusion over about 90 minutes every cycle, about 1 hour every cycle,about 45 minutes every cycle. Each cycle can comprise at least 1 week ofrest, at least 2 weeks of rest, at least 3 weeks of rest. The number ofcycles administered is from about 1 to about 12 cycles, more typicallyfrom about 2 to about 10 cycles, and more typically from about 2 toabout 8 cycles.

In other preferred embodiments, the JNK inhibitor is administered once aweek or every two weeks; chemotherapy is administered daily for severaldays. In other preferred embodiments, chemotherapy is administeredcontinuously for several days to several weeks. In yet other preferredembodiments, chemotherapy is administered in sessions of a few hours toa few days. It is contemplated that such methods include rest periods ofa few weeks where no chemotherapy is administered.

In other preferred embodiments, the JNK inhibitor is administered once aweek or every two weeks; radiation therapy is administered daily forseveral days. In other preferred embodiments, radiation therapy isadministered three times per month for up to eight weeks. In yet otherpreferred embodiments, radiation therapy is administered one day perweek for up to eight weeks. It is contemplated that such methods includerest periods of a few days or a few weeks where no radiation therapy isadministered.

In other preferred embodiments, the JNK inhibitor is administered once aweek or every two weeks; hormonal therapy is administered daily;biological therapy/immunotherapy is administered once a week or everytwo weeks.

In yet other embodiments, the therapeutic and prophylactic agents of theinvention are administered in metronomic dosing regimens, either bycontinuous infusion or frequent administration without extended restperiods. Such metronomic administration can involve dosing at constantintervals without rest periods. Typically the therapeutic agents, inparticular cytotoxic agents, are used at lower doses. Such dosingregimens encompass the chronic daily administration of relatively lowdoses for extended periods of time. In preferred embodiments, the use oflower doses can minimize toxic side effects and eliminate rest periods.In certain embodiments, the therapeutic and prophylactic agents aredelivered by chronic low-dose or continuous infusion ranging from about24 hours to about 2 days, to about 1 week, to about 2 weeks, to about 3weeks to about 1 month to about 2 months, to about 3 months, to about 4months, to about 5 months, to about 6 months. The scheduling of suchdose regimens can be optimalized by the skilled oncologist.

In other embodiments, courses of treatment are administered concurrentlyto a mammal, i.e., individual doses of the therapeutics are administeredseparately yet within a time interval such that the JNK inhibitor canwork together with the other agent or agents. For example, one componentmay be administered one time per week in combination with the othercomponents that may be administered one time every two weeks or one timeevery three weeks. In other words, the dosing regimens for thetherapeutics are carried out concurrently even if the therapeutics arenot administered simultaneously or within the same patient visit.

When used in combination with other prophylactic and/or therapeuticagents, the JNK inhibitor and the prophylactic and/or therapeutic agentcan act additively or, more preferably, synergistically. In oneembodiment, a JNK inhibitor is administered concurrently with one ormore therapeutic agents in the same pharmaceutical composition. Inanother embodiment, a JNK inhibitor is administered concurrently withone or more other therapeutic agents in separate pharmaceuticalcompositions. In still another embodiment, a JNK inhibitor isadministered prior to or subsequent to administration of anotherprophylactic or therapeutic agent.

The invention contemplates administration of a JNK inhibitor incombination with other prophylactic or therapeutic agents by the same ordifferent routes of administration, e.g., oral and parenteral. Incertain embodiments, when a JNK inhibitor is administered concurrentlywith another prophylactic or therapeutic agent that potentially producesadverse side effects including, but not limited to, toxicity, theprophylactic or therapeutic agent can advantageously be administered ata dose that falls below the threshold that the adverse side effect iselicited.

The dosage amounts and frequencies of administration provided herein areencompassed by the terms therapeutically effective and prophylacticallyeffective. The dosage and frequency further will typically varyaccording to factors specific for each patient depending on the specifictherapeutic or prophylactic agents administered, the severity and typeof cancer, the route of administration, as well as age, body weight,response, and the past medical history of the patient. Suitable regimenscan be selected by one skilled in the art by considering such factorsand by following, for example, dosages reported in the literature andrecommended in the Physician's Desk Reference (56^(th) ed., 2002).

In one embodiment, the present invention provides methods of treating orpreventing cancer by administering to a patient in need thereof JNKinhibitors in combination with anti-cancer agents or radiation therapy,wherein the JNK inhibitors have the following Illustrative JNKInhibitors are set forth below.

In one embodiment, the JNK inhibitor has the following structure (I):

wherein:

-   -   A is a direct bond, —(CH₂)_(a)—, —(CH₂)_(b)CH═CH(CH₂)_(c)—, or        —(CH₂)_(b)C≡C(CH₂)_(c)—;    -   R₁ is aryl, heteroaryl or heterocycle fused to phenyl, each        being optionally substituted with one to four substituents        independently selected from R₃;    -   R₂ is —R₃, —R₄, —(CH₂)_(b)C(═O)R₅, —(CH₂)_(b)C(═O)OR₅,        —(CH₂)_(b)C(═O)NR₅R₆, —(CH₂)_(b)C(═O)NR₅(CH₂)_(c)C(═O)R₆,        —(CH₂)_(b)NR₅C(═O)R₆, —(CH₂)_(b)NR₅C(═O)NR₆R₇, —(CH₂)_(b)NR₅R₆,        —(CH₂)_(b)OR₅, —(CH₂)_(b)SO_(d)R₅ or —(CH₂)_(b)SO₂NR₅R₆;    -   a is 1, 2, 3, 4, 5 or 6;    -   b and c are the same or different and at each occurrence        independently selected from 0, 1, 2, 3 or 4;    -   d is at each occurrence 0, 1 or 2;    -   R₃ is at each occurrence independently halogen, hydroxy,        carboxy, alkyl, alkoxy, haloalkyl, acyloxy, thioalkyl,        sulfinylalkyl, sulfonylalkyl, hydroxyalkyl, aryl, arylalkyl,        heterocycle, heterocycloalkyl, —(═O)OR₈, —OC(═O)R₈, —C(═O)NR₈R₉,        —C(═O)NR₈OR₉, —SO₂NR₈R₉, —NR₈SO₂R₉, —CN, —NO₂, —NR₈R₉,        —NR₈C(═O)R₉, —NR₈C(═O)(CH₂)_(b)OR₉, —NR₈C(═O)(CH₂)_(b)R₉,        —O(CH₂)_(b)NR₈R₉, or heterocycle fused to phenyl;    -   R₄ is alkyl, aryl, arylalkyl, heterocycle or heterocycloalkyl,        each being optionally substituted with one to four substituents        independently selected from R₃, or R₄ is halogen or hydroxy;    -   R₅, R6 and R₇ are the same or different and at each occurrence        independently hydrogen, alkyl, aryl, arylalkyl, heterocycle or        heterocycloalkyl, wherein each of R₅, R6 and R₇ are optionally        substituted with one to four substituents independently selected        from R₃; and    -   R₈ and R₉ are the same or different and at each occurrence        independently hydrogen, alkyl, aryl, arylalkyl, heterocycle, or        heterocycloalkyl, or R₈ and R₉ taken together with the atom or        atoms to which they are bonded form a heterocycle, wherein each        of R₈, R₉, and R₈ and R₉ taken together to form a heterocycle        are optionally substituted with one to four substituents        independently selected from R₃.

In one embodiment, -A-R₁ is phenyl, optionally substituted with one tofour substituents independently selected from halogen, alkoxy,—NR₈C(═O)R₉, —C(═O)NR₈R₉, and —O(CH₂)_(b)NR₈R₉, wherein b is 2 or 3 andwherein R₈ and R₉ are defined above.

In another embodiment, R₂ is —R₄, —(CH₂)_(b)C(═O)R₅, —(CH₂)_(b)C(═O)OR₅,—(CH₂)_(b)C(═O)NR₅R₆, —(CH₂)_(b)C(═O)NR₅(CH₂)_(c)C(═O)R₆,—(CH₂)_(b)NR₅C(═O)R₆, —(CH₂)_(b)NR₅C(═O)NR₆R₇, —(CH₂)_(b)NR₅R₆,—(CH₂)_(b)OR₅, —(CH₂)_(b)SO_(d)R₅ or —(CH₂)_(b)SO₂NR₅R₆, and b is aninteger ranging from 0-4

In another embodiment, R₂ is —(CH₂)_(b)C(═O)NR₅R₆, —(CH₂)_(b)NR₅C(═O)R₆,3-triazolyl or 5-tetrazolyl, wherein b is 0 and wherein R₈ and R₉ aredefined above.

In another embodiment, R₂ is 3-triazolyl or 5-tetrazolyl.

In another embodiment:

(a) -A-R₁ is phenyl, optionally substituted with one to foursubstituents independently selected from halogen, alkoxy, —NR₈C(═O)R₉,—(═O)NR₈R₉, and —O(CH₂)_(b)NR₈R₉, wherein b is 2 or 3; and

(b) R₂ is —(CH₂)_(b)C(═O)NR₅R₆, —(CH₂)_(b)NR₅C(═O)R₆, 3-triazolyl or5-tetrazolyl, wherein b is 0 and wherein R₈ and R₉ are defined above.

In another embodiment:

(a) -A-R₁ is phenyl, optionally substituted with one to foursubstituents independently selected from halogen, alkoxy, —NR₈C(═O)R₉,—(═O)NR₈R₉, and —O(CH₂)_(b)NR₈R₉, wherein b is 2 or 3; and

(b) R₂ is 3-triazolyl or 5-tetrazolyl.

In another embodiment, R₂ is R₄, and R₄ is 3-triazolyl, optionallysubstituted at its 5-position with:

(a) a C₁-C₄ straight or branched chain alkyl group optionallysubstituted with a hydroxyl, methylamino, dimethylamino or1-pyrrolidinyl group; or

(b) a 2-pyrrolidinyl group.

In another embodiment, R₂ is R₄, and R₄ is 3-triazolyl, optionallysubstituted at its 5-position with:

methyl, n-propyl, isopropyl, 1-hydroxyethyl, 3-hydroxypropyl,methylaminomethyl, dimethylaminomethyl, 1-(dimethylamino)ethyl,1-pyrrolidinylmethyl or 2-pyrrolidinyl.

In another embodiment, the compounds of Structure (I) have Structure(IA) when A is a direct bond, or have Structure (IB) when A is—(CH₂)_(a)—:

In other embodiments, the compounds of structure (I) have structure (IC)when A is a —CH₂)_(b)CH═CH(CH₂)_(c)—, and have structure (ID) when A is—(CH₂)_(b)C≡C(CH₂)_(c)—:

In further embodiments of this invention, R₁ of structure (I) is aryl orsubstituted aryl, such as phenyl or substituted phenyl as represented bythe following structure (IE):

In another embodiment, R₂ of structure (I) is —(CH₂)_(b)NR₄(C═O)R₅. Inone aspect of this embodiment, b=0 and the compounds have the followingstructure (IF):

Representative R₂ groups of the compounds of structure (I) include alkyl(such as methyl and ethyl), halo (such as chloro and fluoro), haloalkyl(such as trifluoromethyl), hydroxy, alkoxy (such as methoxy and ethoxy),amino, arylalkyloxy (such as benzyloxy), mono- or di-alkylamine (such as—NHCH₃, —N(CH₃)₂ and —NHCH₂CH₃), —NHC(═O)R₄ wherein R₆ is a substitutedor unsubstituted phenyl or heteroaryl (such as phenyl or heteroarylsubstituted with hydroxy, carboxy, amino, alkylester, alkoxy, alkyl,aryl, haloalkyl, halo, —CONH₂ and —CONH alkyl), —NH(heteroarylalkyl)(such as —NHCH₂(3-pyridyl), —NHCH₂(4-pyridyl), heteroaryl (such aspyrazolo, triazolo and tetrazolo), —C(═O)NHR₆ wherein R₆ is hydrogen,alkyl, or as defined above (such as —C(═O)NH₂, —C(═O)NHCH₃,—(═O)NH(H-carboxyphenyl), —(═O)N(CH₃)₂), arylalkenyl (such asphenylvinyl, 3-nitrophenylvinyl, 4-carboxyphenylvinyl),heteroarylalkenyl (such as 2-pyridylvinyl, 4-pyridylvinyl).

Representative R₃ groups of the compounds of structure (I) includehalogen (such as chloro and fluoro), alkyl (such as methyl, ethyl andisopropyl), haloalkyl (such as trifluoromethyl), hydroxy, alkoxy (suchas methoxy, ethoxy, n-propyloxy and isobutyloxy), amino, mono- ordi-alkylamino (such as dimethylamine), aryl (such as phenyl), carboxy,niftro, cyano, sulfinylalkyl (such as methylsulfinyl), sulfonylalkyl(such as methylsulfonyl), sulfonamidoalkyl (such as —NHSO₂CH₃),—NR₈C(═O)(CH₂)_(b)OR₉ (such as NHC(═O)CH₂OCH₃), NHC(═O)R₉ (such as—NHC(═O)CH₃, —NHC(═O)CH₂C₆H₅, —NHC(═O)(2-furanyl)), and —O(CH₂)_(b)NR₈R₉(such as —O(CH₂)₂N(CH₃)₂).

The compounds of structure (I) can be made using organic synthesistechniques known to those skilled in the art, as well as by the methodsdescribed in U.S. application Ser. No. 09/910,950, filed Jul. 23, 2001and International Publication No. WO 02/10137, published Feb. 7, 2002,which are incorporated herein by reference in their entirety(particularly in Examples 1-430, at page 35, line 1 to page 396, line12). Further, specific examples of these compounds are found in theapplication and publication.

In another embodiment, the JNK inhibitor has the following structure(II):

wherein:

-   -   R₁ is aryl or heteroaryl optionally substituted with one to four        substituents independently selected from R₇;    -   R₂ is hydrogen;    -   R₃ is hydrogen or lower alkyl;    -   R₄ represents one to four optional substituents, wherein each        substituent is the same or different and independently selected        from halogen, hydroxy, lower alkyl and lower alkoxy;    -   R₅ and R₆ are the same or different and independently —R₈,        —(CH₂)_(a)C(═O)R₉, —(CH₂)_(a)C(═O)OR₉, —(CH₂)_(a)C(═O)NR₉R₁₀,        —(CH₂)_(a)C(═O)NR₉(CH₂)_(b)C(═O)R₁₀, —(CH₂)_(a)NR₉C(═O)R₁₀,        (CH₂)_(a)NR₁₁C(═O)NR₉R₁₀, —(CH₂)_(a)NR₉R₁₀, —(CH₂)_(a)OR₉,        —(CH₂)_(a)SO_(c)R₉ or —(CH₂)_(a)SO₂NR₉R₁₀;    -   or R₅ and R₆ taken together with the nitrogen atom to which they        are attached to form a heterocycle or substituted heterocycle;    -   R₇ is at each occurrence independently halogen, hydroxy, cyano,        nitro, carboxy, alkyl, alkoxy, haloalkyl, acyloxy, thioalkyl,        sulfinylalkyl, sulfonylalkyl, hydroxyalkyl, aryl, aralkyl,        heterocycle, substituted heterocycle, heterocyclealkyl,        —(═O)OR₈, —OC(═O)R₈, —C(═O)NR₈R₉, —(═O)NR₈OR₉, —SO_(c)R₈,        —SO_(c)NR₈R₉, —NR₈SO_(c)R₉, —NR₈R₉, —NR₈C(═O)R₉,        —NR₈C(═O)(CH₂)_(b)OR₉, —NR₈C(═O)(CH₂)_(b)R₉, —O(CH₂)_(b)NR₈R₉,        or heterocycle fused to phenyl;    -   R₈, R₉, R₁₀ and R₁₁ are the same or different and at each        occurrence independently hydrogen, alkyl, aryl, aralkyl,        heterocycle, heterocyclealkyl;    -   or R₈ and R₉ taken together with the atom or atoms to which they        are attached to form a heterocycle;    -   a and b are the same or different and at each occurrence        independently selected from 0, 1, 2, 3 or 4; and    -   c is at each occurrence 0, 1 or 2.

In one embodiment, R₁ is a substituted or unsubstituted aryl orheteroaryl. When R₁ is substituted, it is substituted with one or moresubstituents defined below. In one embodiment, when substituted, R₁ issubstituted with a halogen, sulfone or sulfonamide.

In another embodiment, R₁ is substituted or unsubstituted aryl, furyl,benzofuranyl, thiophenyl, benzothiophenyl, quinolinyl, pyrrolyl,indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl,benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl,pyrimidinyl, pyrazinyl, triazinyl, cinnolinyl, phthalazinyl orquinazolinyl.

In another embodiment R₁ is substituted or unsubstituted aryl orheteroaryl. When R₁ is substituted, it is substituted with one or moresubstituents defined below. In one embodiment, when substituted, R₁ issubstituted with a halogen, sulfone or sulfonamide.

In another embodiment, R₁ is substituted or unsubstituted aryl,preferably phenyl. When R₁ is a substituted aryl, the substituents aredefined below. In one embodiment, when substituted, R₁ is substitutedwith a halogen, sulfone or sulfonamide.

In another embodiment, R₅ and R₆, taken together with the nitrogen atomto which they are attached form a substituted or unsubstitutednitrogen-containing non-aromatic heterocycle, preferably piperazinyl,piperidinyl or morpholinyl.

When R₅ and R₆, taken together with the nitrogen atom to which they areattached form substituted piperazinyl, piperadinyl or morpholinyl, thepiperazinyl, piperadinyl or morpholinyl is substituted with one or moresubstituents defined below. In one embodiment, when substituted, thesubstituent is alkyl, amino, alkylamino, alkylether, acyl, pyrrolidinylor piperidinyl.

In one embodiment, R₃ is hydrogen and R₄ is not present, and thecompounds have the following structure (IIA):

and pharmaceutically acceptable salts thereof.

In a more specific embodiment, R₁ is phenyl optionally substituted withR₇, and having the following structure (IIB):

and pharmaceutically acceptable salts thereof.

In still a further embodiment, R₇ is at the para position of the phenylgroup relative to the pyrimidine, as represented by the followingstructure (IIC):

and pharmaceutically acceptable salts thereof.

The compounds of structure (II) can be made using organic synthesistechniques known to those skilled in the art, as well as by the methodsdescribed in U.S. application Ser. No. 10/004,645, filed Dec. 4, 2001,and International Publication No. WO 02/46170, published Jun. 13, 2002,which are hereby incorporated by reference in their entirety(particularly Examples 1-27 at page 23, line 5 to page 183, line 25).Further, specific examples of these compounds are found in saidapplication and publication.

In another embodiment, the JNK inhibitor has the following structure(III):

-   -   wherein R₀ is —O—, —S—, —S(O)—, —S(O)₂—, NH or —CH₂—;

the compound being (i) unsubstituted, (ii) monosubstituted and having afirst substituent, or (iii) disubstituted and having a first substituentand a second substituent;

the first or second substituent, when present, is at the 3, 4, 5, 7, 8,9, or 10 position, wherein the first and second substituent, whenpresent, are independently alkyl, hydroxy, halogen, nitro,trifluoromethyl, sulfonyl, carboxyl, alkoxycarbonyl, alkoxy, aryl,aryloxy, arylalkyloxy, arylalkyl, cycloalkylalkyloxy, cycloalkyloxy,alkoxyalkyl, alkoxyalkoxy, aminoalkoxy, mono-alkylam inoalkoxy,di-alkylaminoalkoxy, or a group represented by formula (a), (b), (c),(d), (e), or (f):

wherein R₃ and R₄ are taken together and represent alkylidene or aheteroatom-containing alkylidene or R₃ and R₄ are independentlyhydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl,aryloxyalkyl, alkoxyalkyl, aminoalkyl, mono-alkylaminoalkyl, ordi-alkylaminoalkyl; and

R₅ is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl,alkoxy, alkoxyalkyl, alkoxycarbonylalkyl, amino, mono-alkylamino,di-alkylamino, arylamino, arylalkylamino, cycloalkylamino,cycloalkylalkylamino, aminoalkyl, mono-alkylaminioalkyl, ordi-alkylaminoalkyl; or a pharmaceutically acceptable salt thereof.

In another embodiment, the JNK inhibitor has the following structure(IV):

wherein:

R₁ is selected from hydrogen, C₁₋₆ alkyl (optionally substituted by oneor two substituents independently selected from halo, amino, C₁₋₄alkylamino, di-(C₁₋₄ alkyl)amino, hydroxy, cyano, C₁₋₄ alkoxy, C₁₋₄alkoxy, C₁₋₄ alkoxycarbonyl, carbamoyl, —NHCOC₁₋₄ alkyl,trifluoromethyl, phenylthio, phenoxy, pyridyl, morpholino), benzyl,2-phenylethyl, C₃₋₅ alkenyl (optionally substituted by up to three halosubstituents, or by one trifluoromethyl substituent, or one phenylsubstituent), N-phthalimido-C₁₋₄ alkyl, C₃₋₅ alkynyl (optionallysubstituted by one phenyl substitutent) and C₃₋₆ cycloalkyl-C₁₋₆ alkyl;wherein any phenyl or benzyl group in R¹ is optionally substituted by upto three substituents independently selected from halo, hydroxy, nitro,amino, C₁₋₃ alkylamino, di-(C₁₋₃ alkyl) alkyl) amino, cyano,trifluoromethyl, C₁₋₃alkyl (optionally substituted by 1 or 2substituents independently selected from halo, cyano, amino, C₁₋₃alkylamino, di-(C₁₋₃ alkyl) amino, hydroxy and trifluoromethyl), C₁₋₃alkenyl (optionally substituted by up to three halo substituents, or byone trifluoromethyl substituent), C₃₋₅ alkynyl, C₁₋₃ alkoxy, mercapto,C₁₋₃ alkylthio, carboxy, C₁₋₃ alkoxycarbonyl;

R^(x) is selected from halo, hydroxy, nitro, amino, cyano, mercapto,carboxy, sulphamoyl, formamido, ureido or carbamoyl or a group ofstructure (IVb):A-B-C  (IVb)wherein:

A is C₁₋₆ alkyl, C₂₋₆ alkenyl, C₁₋₆ alkynyl, C₃₋₈ cycloalkyl, phenyl,heterocycle or heteroaryl, wherein said C₁₋₆ alkyl, C₃₋₆ alkynyl are areoptionally substituted by one or more substituents selected from halo,nitro, cyano, amino, hydroxy, mercapto, carboxy, formamido, ureido, C₁₋₃alkylamino, di-(C₁₋₃ alkyl) amino, C₁₋₃ trifluoromethyl, C₃₋₈cycloalkyl, phenyl, heterocycle or heteroaryl; wherein any phenyl, C₃₋₈cycloalkyl, heterocycle or heteroaryl may be optionally substituted byone or more halo, nitro, cyano, hydroxy, trifluoromethyl, trifluorometlioxy, amino, carboxy, carbamoyl, mercapto, formamido, ureido,sulphamoyl, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkoxy, C₁₋₄alkanoyl, C₁₋₄ alkanoyloxy, C₁₋₄ alkylamino, di-(C₁₋₄ alkyl)amino, C₁₋₄alkanoylamino, N—C₁₋₄ alkylcarbamoyl, N,N-di-(C₁₋₄ alkyl)carbamoyl, C₁₋₄alkylthio, C₁₋₄ alkylsulphinyl, C₁₋₄ alkylsulphonyl and C₁₋₄alkoxycarbonyl;

B is —O—, -5-, —C(O)—, —NH—, —N(C₁₋₄ alkyl)-, —C(O)NH—, —C(O)N(C₁₋₄alkyl)-, NHC(O)—, —N(C₁₋₄ alkyl)C(O)— or B is a direct bond;

C is C₁₋₄ alkylene or a direct bond;

Q₁ and Q₂ are independently selected from aryl, a 5- or 6-memberedmonocyclic moiety (linked via a ring carbon atom and containing one tothree heteroatoms independently selected from nitrogen, oxygen andsulphur); and a 9- or 10-membered bicyclic heterocyclic moiety (linkedvia a ring carbon atom and containing one or two nitrogen heteroatomsand optionally containing a further one or two heteroatoms selected fromnitrogen, oxygen and sulphur);and one or both of Q₁ and Q₂ is substituted on any available carbon atomwith one substituent of the structure (IVa) and Q₂, may optionally befurther substituted on any available carbon atom with a substituent ofthe structure (IVa):

(provided that when present in Q₁ the substituent of formula (IVa) isnot adjacent to the —NH-link);wherein:

X is —CH₂—, —O—, —NH—, —NR^(y)— or —S— (wherein R^(y) is C₁₋₄ alkyl,optionally substituted by one substituent selected froni halo, amino,cyano, C₁₋₄ alkoxy or hydroxy);

Y¹ is H, C₁₋₄ alkyl or as defined for Z;

Y² is H or C₁₋₄ alkyl;

Z is R³O—, R^(b)R^(c)N—, R^(d)S—, R^(e)R^(f)NNR^(g)—, a nitrogen linkedheteroaryl or a nitrogen linked heterocyclic (wherein said heterocycleis optionally substituted on a ring carbon or a ring nitrogen by C₁₋₄alkyl or C₂₋₄ alkanoyl) wherein R^(a), R^(b), R^(c), R^(d), R^(e), R^(f)and R⁹ are independently selected from hydrogen, C₁₋₄ alkyl, C₂₋₄alkenyl, C₃₋₈ cycloalkyl, and wherein said C₁₋₄ alkyl and C₂₋₄ alkenylare optionally substituted by one or more phenyl;

n is 1, 2 or 3;

m is 1, 2 or 3;

and Q₁ may optionally be substituted on any available carbon atom withup to four substituents independently selected from halo, thio, nitro,carboxy, cyano, C₂₋₄ alkenyl (optionally substituted by up to three halosubstituents, or by one trifluoromethyl substituent), C₂₋₄ alkynyl, C₁₋₅alkanoyl, C₁₋₄ alkoxycarbonyl, C₁₋₅ alkyl, hydroxy-C₁₋₃ alkyl,fluoro-C₁₋₄ alkyl, amino-C₁₋₃ alkyl, C₁₋₄ alkylamino-C₁₋₃ alkyl,di-(C₁₋₄ alkyl)amino-C₁₋₃ alkyl, cyano-C₁₋₄ alkyl, C₂₋₄ alkanoyloxy-C₁₋₄alkyl, C₁₋₄ alkoxy-C₁₋₃ alkyl, carboxy-C₁₋₄ alkyl, C₁₋₄alkoxycarbonyl-C₁₋₄ alkyl, carbamoyl-C₁₋₄ alkyl, N—C₁₋₄alkylcarbamoyl-C₁₋₄ alkyl, N,N-di-(C₁₋₄ alkyl)-carbamoyl-C₁₋₄ alkylpyrrolidin-1-yl-C₁₋₃ alkyl, piperidino-C₁₋₃ alkyl, piperazin-)-yl-C₁₋₃alkyl, morpholino-C₁₋₃ alkyl, thiomorpholino-C₁₋₃ alkyl,imidazo-1-yl-C₁₋₃ alkyl, piperazin-1-yl, morpholino, thiomorpholino-C₁₋₄alkylthio, C₁₋₄ alkylsulphinyl, C₁₋₄ alkylsulphonyl, hydroxy C₂₋₄alkylthio, hydroxy C₂₋₄ alkylsulphinyl, hydroxy C₂₋₄ alkylsulphonyl,ureido, N′-(C₁₋₄ alkyl)ureido, N′-N′-di-(C₁₋₄ alkyl)ureido, N′-(C₁₋₄alkyl)-N-(C₁₋₄ alkyl)ureido, N′,N′-di-(C₁₋₄ alkyl)-N-(C₁₋₄ alkyl)ureido,carbamoyl, N-(C₁₋₄ alkyl)carbamoyl, N,N-di-(C₁₋₄ alkyl)carbamoyl, amino,C₁₋₄ alkylamino, di-(C₁₋₄ alkyl)amino, C₂₋₄ alkanoylamino, sulphamoyl,N-(C₁₋₄ alkyl)sulphamoyl, N,N-di-(C₁₋₄ alkyl)sulphamoyl;

and also independently, or where appropriate in addition to, the abovesubstituents, Q₁ may optionally be substituted on any available carbonatom up with to two further substituents independently selected fromC₃₋₈ cycloalkyl, phenyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkoxy, phenylthio,phenyl, naphthyl, benzoyl, benzimidazol-2-yl, phenoxy and a 5- or6-membered aromatic heterocycle (linked via a ring carbon atom andcontaining one to three heteroatoms independently selected from oxygen,sulphur and nitrogen); wherein said naphthyl, phenyl, benzoyl, phenoxy,5- or 6-membered aromatic heterocyclic substituents and the phenyl groupin said phenyl-C₁₋₄ alkyl, phenylthio and phenyl-C₁₋₄ alkoxysubstituents may optionally be substituted with up to five substituentsindependently selected from halo, C₁₋₄ alkyl and C₁₋₄ alkoxy;

and Q₂ may optionally be substituted on any available carbon atom withup to four substituents independently selected from halo, hydroxy, thio,nitro, carboxy, cyano, C₂₋₄ alkenyl (optionally substituted by up tothree halo substituents, or by one trifluoromethyl substituent), C₂₋₄alkynyl, C₁₋₅ alkanoyl, C₁₋₄ alkoxycarbonyl, C₁₋₆ alkyl, hydroxy-C₁₋₃alkyl, fluoro-C₁₋₄ alkyl, amino-C₁₋₃ alkyl, C₁₋₄ alkylarnino-C₁₋₃ alkyl,di-(C₁₋₄ alkyl)amino-C₁₋₃ alkyl, cyano-C₁₋₄ alkyl, C₂₋₄ alkanoyloxy-C₁₋₄alkyl, C₁₋₄ alkoxy-C₁₋₃ alkyl, carboxy-C₁₋₄ alkyl, C₁₋₄alkoxycarbonyl-C₁₋₄ alkyl, carbamoyl-C₁₋₄ alkyl, N-(C₁₋₄alkylcarbamoyl-C₁₋₄ alkyl, N,N-di-(C₁₋₄ alkyl)-carbamoyl-C₁₋₄ alkylpyrrolidin-1-yl-C₁₋₃ alkyl, piperidino-C₁₋₃ alkyl, piperazin-)-yl-C₁₋₃alkyl, morpholino-C₁₋₃ alkyl, thiomorpholino-C₁₋₃ alkyl,imidazo-1-yl-C₁₋₃ alkyl, piperazin-1-yl, morpholino, thiomorpholino,C₁₋₄ alkoxy, cyano-C₁₋₄ alkoxy, carbamoyl-C₁₋₄ alkoxy N′-(C₁₋₄alkylcarbamoyl, C₁₋₄ alkyl)alkoxy, N,N-di-(C₁₋₄ alkyl)-carbamoyl-C₁₋₄alkyl, 2-aminoethoxy, 2-C₁₋₄ alkylaminoethoxy,2-di-(C₁₋₄alkyl)aminoethoxy, C₁₋₄ alkoxycarbonyl-C₁₋₄ alkoxy, halo-C₁₋₄alkoxy, 2-hydroxyethoxy, C₂₋₄ alkanoyloxy-C₁₋₄ alkoxy, 2-C₁₋₄alkoxyethoxy, carboxy-C₁₋₄ alkoxy, 2-pyrrolidin-1-yl-ethoxy,2-piperidino-ethoxy, 2-piperazin-1-yl-ethoxy, 2-morpholino-ethoxy,2-thiomorpholino-ethoxy, 2-imidazo-1-yl-ethoxy, C₃₋₅ alkenyloxy, C₃₋₅alkynyloxy, C₁-C₄ alkylthio, C₁₋₄ alkylsulphinyl, C₁₋₄ alkylsulphonyl,hydroxy C₂₋₄ alkylthio, hydroxy C₂₋₄-alkylsulphinyl, hydroxy C₂₋₄alkylsulphonyl, ureido, N′-(C₁₋₄ alkyl)ureido, N′,N′-di-(C₁₋₄alkyl)ureido, N′-(C₁₋₄ alkyl)-N-(C₁₋₄ alkyl)ureido, N′,N′-di-(C₁₋₄alkyl)-N-(C₁₋₄ alkyl)ureido, carbamoyl, N′-(C₁₋₄ alkyl)carbamoyl,N,N-di-(C₁₋₄ alkyl)carbamoyl, amino, C₁₋₄ alkylamino, di-(C₁₋₄alkyl)amino, C₂₋₄ alkanoylamino, sulphamoyl, N-(C₁₋₄ 4alkyl)sulphamoyl,N,N-di-(C₁₋₄ alkyl)sulphamoyl, and also independently, or whereappropriate in addition to, the above optional substituents, Q₂ mayoptionally be substituted on any available carbon atom with up to twofurther substituents independently selected from C₃₋₈ cycloalkyl,phenyl-C₁₋₄ alkyl, phenyl-C₁₋₄-alkoxy, phenylthio, phenyl, naphthyl,benzoyl, phenoxy, benzimidazol-2-yl, and a 5- or 6-membered aromaticheterocycle (linked via a ring carbon atom and containing one to threeheteroatoms independently selected from oxygen, sulphur and nitrogen);wherein said naphthyl, phenyl, benzoyl, phenoxy, 5- or 6-memberedaromatic heterocyclic substituents and the phenyl group in saidphenyl-C₁₋₄ alkyl, phenylthio and phenyl-C₁₋₄ alkoxy substituents mayoptionally be substituted with one or two substituents independentlyselected from halo, C₁₋₄ alkyl and C₁₋₄ alkoxy.

The compounds of structure (IV) can be made using organic synthesistechniques known to those skilled in the art, as well as by the methodsdescribed in International Publication No. WO 00/39101, which isincorporated herein by reference in its entirety (particularly at page2, line 10 to page 6, line 12). Further, specific examples of thesecompounds can be found in this publication.

In another embodiment, the JNK inhibitor has the following structure(V):

wherein:

Ring A is imidazo(1,2a)pyrid-3-yl or pyrazolo(2,3a)pyrid-3-yl;

R² is attached to a ring carbon and is selected from halo, nitro, cyano,hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl,mercapto, sulphamoyl, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆alkoxy, C₁₋₆ alkanoyl, C₁₋₆ alkanoyloxy, N-(C₁₋₆ alkyl)amino, N,N-(C₁₋₆alkyl)amino, C₁₋₆ alkanoylamino, N-(C₁₋₆ alkyl)carbamoyl, N,N-(C₁₋₆alkyl)₂ carbamoyl, C₁₋₆ alkylS(O)_(a) wherein a is 0 to 2, C₁₋₆alkoxycarbonyl, N-(C₁₋₆ alkyl)sulphamoyl, N,N-(C₁₋₆ alkyl)₂ sulphamoyl,phenyl, heterocyclic group, phenylthio or (heterocyclic group)thio;wherein any C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl orheterocyclic group may be optionally substituted on carbon by one ormore G; and wherein if said heterocyclic group contains an —NH— moietythat nitrogen may be optionally substituted by a group selected from Q;

m is 0-5; wherein the values of R² may be the same or different;

R¹ is halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy,amino, carboxy, carbamoyl, mercapto, sulphamoyl, C₁₋₃ alkyl, C₂₋₃alkenyl, C₂₋₃ alkynyl, C₁₋₃ alkoxy, C₁₋₃ alkanoyl, N-(C₁₋₃ alkyl)amino,N,N-(C₁₋₂ alkyl)₂ amino, C₁₋₃ alkanoylamino, N-(C₁₋₃ alkyl)carbamoyl,N,N-(C₁₋₂ alkyl)₂ carbamoyl, C₁₋₃ alkylS(O)_(a) wherein a is 0 to 2,N-(C₁₋₃ alkyl)sulphamoyl or N,N-(C₁₋₃ alkyl)₂ sulphamoyl; wherein anyC₁₋₂ alkyl, C₁₋₃ alkyl, C₂₋₃ alkenyl or C₂₋₃ alkynyl may be optionallysubstituted on carbon by one or more J;

n is 0 to 2; wherein the values of R¹ may be the same or different;

Ring B is phenyl or phenyl fused to a C₅₋₇ cycloalkyl ring;

R³ is halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto,sulphamoyl, C₂₋₆alkenyl or C₂₋₆ alkynyl;

p is 0-4; wherein the values of R³ may be the same or different;

R⁴ is a group A-E; wherein

A is selected from C₁₋₆ alkyl, phenyl, a heterocyclic group, C₃₋₈cycloalkyl, phenylC₁₋₆ alkyl, (heterocyclic group)C₁₋₆ alkyl or C₃₋₈cycloalkyl C₁₋₆ cycloalkyl; which C₁₋₆ alkyl, phenyl, a heterocyclicgroup, C₃₋₈ cycloalkyl, phenyl C₁₋₆ alkyl, (heterocyclic group) C₁₋₆alkyl, or C₃₋₈ cycloalkyl-C₁₋₆ cycloalkyl may be optionally substitutedon carbon by one or more D; and wherein if said heterocyclic groupcontains an —NH— moiety that nitrogen may be optionally substituted by agroup selected from R;

E is a direct bond or —O—, —C(O)—, —OC(O)—, —C(O)O—, —N(R^(a))C(O)—,—C(O)N(R^(a))—, —N(R^(a))—, —S(O)_(r)—, —SO₂N(R^(a))— or N(R^(a))SO₂—;wherein R^(a) is hydrogen or C₁₋₆ alkyl optionally substituted by one ormore D and r is 0-2;

D is independently selected from oxo, halo, nitro, cyano, hydroxy,trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto,sulphamoyl, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₁₋₆ alkoxy, C₁₋₆ alkanoyl, C₁₋₆alkanoyloxy, N-(C₁₋₆ alkyl)amino, N,N-(C₁₋₆ alkyl)₂ amino, C₁₋₆alkanoylamino, N-(C₁₋₆ alkyl)carbamoyl, N,N-(C₁₋₆ alkyl)₂ carbarnoyl,C₁₋₆ alkylS(O)_(a) wherein a is 0 to 2, C₁₋₆ alkoxycarbonyl, C₁₋₆alkoxycarbonylamino, benzyloxcarbonylamino, N-(C₁₋₆ alkyl)sulphamoyl andN,N-(C₁₋₆ alkyl)₂ sulphamoyl; wherein any C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl or phenyl may be optionally substituted on carbon by one or moreK;

q is 0-2; wherein the values of R⁴ may be the same or different; andwhrein p+q≦5;

G, J and K are independently selected from halo, nitro, cyano, hydroxy,trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto,sulphamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy,methylamino, ethylamino, dimethylamino, diethylamino,N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl,methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl,ethylsulphonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulphamoyl,N-ethylsulphamoyl, N,N-dimethylsulphamoyl, N,N-diethylsulphamoyl orN-methyl-N-ethylsulphamoyl; and

Q and R are independently selected from C₁₋₄ alkyl, C₁₋₄ alkanoyl, C₁₋₄alkylsulphonyl, C₁₋₄ alkoxycarbonyl,carbamoyl, N-(C₁₋₄ alkyl)carbamoyl,N,N-(C₁₋₄ alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl andphenylsulphonyl; or pharmaceutically acceptable in vivo hydrolyzableesters, analogs, hydrolysis products, metabolites, salts, solvates,hydrates, clathrates, polymorphs, stereoisomers, derivatives andprecursors thereof.

The compounds of structure (V) can be made using organic synthesistechniques known to those skilled in the art, as well as by the methodsdescribed in International Publication No. WO 01/14375, which isincorporated herein by reference in its entirety (particularly at page2, line 4 to page 4, line 4). Further, specific examples of thesecompounds can be found in this publication.

In another embodiment, the JNK inhibitor has the following structure(VI):

wherein:

G is N, CH or C(CN);

ring X is a 5- or 6-membered fused heteroaryl ring which contains 1, 2or 3 heteroatoms selected from oxygen, sulphur and nitrogen;

m is 0, 1 or 2;

R¹ is hydroxy, halo, trifluoromethyl, cyano, mercapto, nitro, amino,carboxy, carbamoyl, formyl, sulphamoyl, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ alkoxy, —O—(C₁₋₃ alkyl)-O—, C₁₋₆ alkylS(O)_(a)— (wherein nis 0-2), N-(C₁₋₆ alkylamino, N,N-(C₁₋₆ alkyl)₂amino, C₁₋₆alkoxycarbonyl, N-(C₁₋₆ alkylcarbamoyl, N,N-(C₁₋₆ alkyl)₂ carbamoyl,C₂₋₆ alkanoyl, C₁₋₆ alkanoyloxy, C₁₋₆ alkanoylarnino, N-(C₁₋₆alkylsulphamoyl, N,N-(C₁₋₆ alkyl)₂ sulphamoyl, C₁₋₆ alkylsulphonylamino,C₁₋₆ alkylsulphonyl-N-(C₁₋₆ alkyl)amino, or R¹ is of the Structure (IA):A-(CH₂)_(p-)B—  (VIA)wherein A is halo, hydroxy, C₁₋₆ alkoxy, C₁₋₆ alkylS(O)_(n)— (wherein nis 0-2), cyano, amino, N-(C₁₋₆ alkylamino, N,N-(C₁₋₆ alkyl)₂ amino,carboxy, C₁₋₆ alkoxycarbonyl, carbamoyl, N-C₁₋₆ alkylcarbamoyl orN,N-(C₁₋₆ alkyl)₂ carbamoyl, p is 1-6, and B is a bond, oxy, imino,N-(C₁₋₆ alkyl)imino or —C(O)NH—, or R¹ is of the Structure (VIB):D-E-  (VIB)wherein D is aryl, heteroaryl or heterocyclyl and E is a bond, C₁₋₆alkylene, C₁₋₆ alkyleneoxy, oxy, imino, N-(C₁₋₆ alkyl)imino, C₁₋₆alkyleneimino, N-(C₁₋₆ alkyl)-C₁₋₆ alkyleneimino, C₁₋₆ alkyleneoxy-C₁₋₆alkylene, C₁₋₆ alkyleneimino-C₁₋₆ alkylene, N-(C₁₋₆ alkyl)- C₁₋₆alkyleneimino-C₁₋₆ alkylene, —C(O)NH—, —SO₂NH—, —NHSO₂— or C₂₋₆alkanoylimino, and any aryl, heteroaryl or heterocyclyl group in a R¹group may be optionally substituted with one or more groups selectedfrom hydroxy, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, carboxy, C₁₋₆alkoxycarbonyl, carbamoyl, N-(C₁₋₆ alkylcarbamoyl, N-(C₁₋₆ alkyl),carbamoyl, C₂₋₆ alkanoyl, amino, N-(C₁₋₆ alkylamino and N,N-(C₁₋₆alkyl),amino,

and any heterocyclyl group in a R¹ group may be optionally substitutedwith one or two oxo or thioxo substituents,

and any of the R¹ groups defined hereinbefore which comprises a CH₂group which is attached to 2 carbon atoms or a CH₃ group which isattached to a carbon atom may optionally be substituted on each said CH₂or CH₃ group with a substituent selected from hydroxy, amino, C₁₋₆alkoxy, N-(C₁₋₆ alkylamino, N,N-(C₁₋₆ alkyl),amino and heterocyclyl;

R² is hydrogen, halo, C₁₋₆ alkyl, C₁₋₆ alkenyl or C₂₋₆ alkynyl;

R³ is hydrogen, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl;

R⁴ is hydrogen, hydroxy, C₁₋₆ alkyl, C₁₋₆ alkoxy, amino, N-(C₁₋₆alkylamino, N,N-(C₁₋₆ alkyl)₂ amino, hydroxy-C₂₋₆ alkoxy, C₁₋₆alkoxyC₂₋₆ alkoxy, amino-C₂₋₆ alkoxy, N-(C₁₋₆ alkylaminoC₂₋₆ alkoxy,N,N-(C₁₋₆ alkyl), amino-C₂₋₆ alkoxy or C₃₋₇ cycloalkyl, or R⁴ is or theStructure (VIC):—K-J  (VIC)wherein J is aryl, heteroaryl or heterocyclyl and K is a bond, oxy,imino, N-(C₁₋₆ alkyl)imino, oxy-C₁₋₆ alkylene, imino-C₁₋₆ alkylene,N-(C₁₋₆ alkyl)imino-C₁₋₆ alkylene, —NHC(O)—, —SO₂NH—, —NHSO₂— or—NHC(O)—C₁₋₆ alkylene-,

and any aryl, heteroaryl or heterocyclyl group in a R⁴ group may beoptionally substituted by one or more groups selected from hydroxy,halo, trifluoromethyl, cyano, mercapto, nitro, amino, carboxy,carbamoyl, formyl, sulphamoyl, C₁₋₆ alkyl, C₁₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ alkoxy, —O-(C₁₋₃ alkyl)-O—, C₁₋₆ alkylS(O)_(n)— (wherein n is 0-2),N-(C₁₋₆ alkylamino, N,N-(C₁₋₆ alkyl)₂amino, C₁₋₆ alkoxycarbonyl, N-(C₁₋₆alkylcarbamoyl, N,N-(C₁₋₆ alkyl)₂ carbamoyl, C₁₋₆ alkanoyl, C₁₋₆alkanoyloxy, C₁₋₆ alkanoylamino, N-(C₁₋₆ alkylsulphamoyl, N,N-(C₁₋₆alkyl)₂ sulphamoyl, C₁₋₆ alkylsulphonylamino and C₁₋₆alkylsulphonyl-N-(C₁₋₆ alkyl)amino, or any aryl, heteroaryl orheterocyclyl group in a R⁴ group may be optionally substituted with oneor more groups of the Structure (VIA¹):—B¹—(CH₂)_(p-)A¹  (VIA¹)wherein A¹ is halo, hydroxy, C₁₋₆ alkoxy, cyano, amino, N-(C₁₋₆alkylamino, N,N-(C₁₋₆ alkyl)₂ amino, carboxy, C₁₋₆ alkoxycarbonyl,carbamoyl, N-(C₁₋₆ alkylcarbamoyl or N,N-(C₁₋₆ alkyl)₂carbamoyl, p is1-6, and B¹ is a bond, oxy, imino, N-(C₁₋₆ alkyl)imino or —NHC(O)—, withthe proviso that p is 2 or more unless B¹ is a bond or —NHC(O)—, or anyaryl, heteroaryl or heterocyclyl group in a R⁴ group may be optionallysubstituted with one or more groups of the Structure (VIB¹):-E¹-D¹  (VIB′)wherein D¹ is aryl, heteroaryl or heterocyclyl and E¹ is a bond, C₁₋₆alkylene, oxy-C₁₋₆ alkylene, oxy, imino, N-(C₁₋₆ alkyl)imino, imino-C₁₋₆alkylene, N-(C₁₋₆ alkyl)-iminoC₁₋₆ alkylene, C₁₋₆ alkylene-Oxy-C₁₋₆alkylene, C₁₋₆ alkylene-imino-C₁₋₆ alkylene, C₁₋₆ alkylene-N-(C₁₋₆alkyl)-imino-C₁₋₆ alkylene, —NHC(O)—, —NHSO₂—, —SO₂NH— or —NHC(O)—C₁₋₆alkylene-, and any aryl, heteroaryl or heterocyclyl group in asubstituent on R⁴ may be optionally substituted with one or more groupsselected from hydroxy, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, carboxy, C₁₋₆alkoxycarbonyl, carbamoyl, N-(C₁₋₆ alkylcarbamoyl, N-(C₁₋₆ alkyl)₂carbamoyl, C₂₋₆ alkanoyl, amino, N-(C₁₋₆ alkylamino and N,N-(C₁₋₆alkyl)₂ amino, and any C₃₋₇ cycloalkyl or heterocyclyl group in a R⁴group may be optionally substituted with one or two oxo or thioxosubstituents, and any of the R⁴ groups defined hereinbefore whichcomprises a CH₂ group which is attached to 2 carbon atoms or a CH₃ groupwhich is attached to a carbon atom may optionally be substituted on eachsaid CH₂ or CH₃ group with a substituent selected from hydroxy, amino,C₁₋₆ alkoxy, N-(C₁₋₆ alkylamino, N,N-(C₁₋₆ alkyl)₂amino andheterocyclyl;

R⁵ is hydrogen, halo, trifluoromethyl, cyano, nitro, amino, hydroxy,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, N-(C₁₋₆ alkylaminoor N,N-(C₁₋₆ alkyl)₂amino; q is 0, 1, 2, 3 or 4.

The compounds of structure (VI) can be made using organic synthesistechniques known to those skilled in the art, as well as by the methodsdescribed in International Publication No. WO 00/56738, which isincorporated herein by reference in its entirety (particularly at page3, line 25 to page 6, line 13). Further, specific examples of thesecompounds can be found in this publication.

In another embodiment, the JNK inhibitor has the following structure(VII):

wherein m is 0, 1, 2 or 3 and R¹ group, which may be the same ordifferent, is selected from hydroxy, halogen, trifluoromethyl, cyano,mercapto, nitro, amino, carboxy, carbamoyl, formyl, sulphamoyl, C₁₋₆alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₆ alkoxycarbonyl, N-C₁₋₆alkylcarbamoyl, N,N-di-(C₁₋₆ alkyl)carbamoyl, C₂₋₆ alkanoyl, C₂₋₆alkanoyloxy, C₂₋₆ alkanoylamino, N-C₁₋₆ alkyl-C₂₋₆ alkanoylamino, N-C₁₋₆alkylsulphamoyl, N, N-di(C₁₋₆ alkyl)sulphamoyl, C₁₋₆alkanesulphonylamino and N-C₁₋₆ alkanesulphonylamino, or from a group ofthe structure:Q²-X¹—wherein X¹ is a direct bond or is selected from O, S, SO, SO₂, N(R⁴),CO, CH(OR⁴), CON(R⁴), N(R⁴)CO, SO₂N(R⁴), N(R⁴)SO₂, OC(R⁴)₂, SC(R⁴)₂, andN(R⁴)C(R⁴)₂, wherein each R⁴ is hydrogen or C₁₋₆ alkyl, and Q² is aryl,C₁₋₆ alkyl, heteroaryl-C₁₋₆ alkyl, heterocyclyl or heterocyclyl-C₁₋₆alkyl, or (R¹⁾ _(m) is C₁₋₃ alkylenedioxy,

and wherein a single pair of adjacent carbon atoms in a C₂₋₆ alkylenechain within a R¹ substitutent is optionally separated by the insertionof a group selected from O, S, SO, SO₂, N(R⁵), CO, CH(OR⁵), CON(R⁵),N(R⁵)CO, SO₂N(R⁵) and N(R⁵)SO₂ wherein R⁵ is hydrogen or C₁₋₆ alkyl,

and wherein any aryl, heteroaryl or heterocyclyl group within asubstituent on R¹ optionally is substituted with 1, 2 or 3 substituents,which may be the same or different, selected from halogeno,trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, C₁₋₆alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₆ alkylsulphinyl, C₁₋₆alkylsulphonyl, C₁₋₆ alkylamino, di-(C₁₋₆ alkyl)amino, C₁₋₆alkoxycarbonyl, N-C₁₋₆ alkylcarbamoyl, N,N-di-(C₁₋₆ alkyl)carbamoyl,C₂₋₆ alkanoyl, C₁₋₆ alkanoyloxy, C₁₋₆ alkanoylamino, N-C₁₋₆ alkyl-C₁₋₆alkanoylamino, N-C₁₋₆ alkylsulphamoyl, N,N-di-(C₁₋₆ alkyl)sulphamoyl,C₁₋₆ alkanesulphonylamino and N-C₁₋₆ alkyl-C₁₋₆ alkanesulphonylamino, orfrom a group of the structure:—X²-Q³wherein X² is a direct bond or is selected from O and N(R), wherein R⁷is hydrogen or C₁₋₆ alkyl, and Q³ is aryl, aryl-C₁₋₆ alkyl, heteroaryl,heteroaryl-C₁₋₆ alkyl, heterocyclyl or heterocyclyl-C₁₋₆ alkyl, and anygroup optionally is substituted with 1 or 2 substituents, which may bethe same or different, selected from halogeno, trifluoromethyl, cyano,hydroxy, amino, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino and di-(C₁₋₆alkyl)amino,

and wherein any heterocyclyl group within a substituent on R′ optionallyis substituted with 1 or 2 oxo or thioxo substituents,

and wherein any CH₂ or CH₃ group within a R¹ substituent optionally issubstituted with on each said CH₂ or CH₃ group one or more halogeno orC₁₋₆ alkyl substituents or a substituent selected from hydroxy, cyano,amino, carboxy, carbamoyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₆alkylsulphinyl, C₁₋₆ alkylsulphonyl, C₁₋₆ alkylamino, di-(C₁₋₆alkyl)amino, C₁₋₆ alkoxycarbonyl, N-C₁₋₆ alkylcarbamoyl, N,N-di-(C₁₋₆alkyl)carbamoyl, C₂₋₆ alkanoyl, C₂₋₆ alkanoyloxy, C₂₋₆ alkanoylamino,N-C₁₋₆ alkyl-C₁₋₆ alkanoylamino, N-C₁₋₆ alkylsulphamoyl, N,N-di-(C₁₋₆alkyl)sulphamoyl, C₁₋₆ alkanesulphonylamino and N-C₁₋₆ alkyl-C₁₋₆alkanesulphonylamino;

R³ is hydrogen, halogeno or C₁₋₆ alkyl;

n is 0, 1 or 2 and each R² group, which may be the same or different, isselected from hydroxy, halogeno, trifluoromethyl, cyano, mercapto,nitro, amino, carboxy, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkyl, C₁₋₆ alkoxy,C₁₋₆ alkylamino and di-(C₁₋₆ alkyl)amino;

p is 0, 1, 2,3 or 4; and

Q¹ is aryl or heteroaryl and Q¹ is optionally substituted with 1, 2 or 3substituents, which may be the same or different, selected from hydroxy,halogen, trifluoromethyl, cyano, mercapto, nitro, amino, carboxy,carbamoyl, formyl, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₆alkylsulphinyl, C₁₋₆ alkylsulphonyl, C₁₋₆ alkylamino, di-(C₁₋₆alkyl)amino, C₁₋₆ alkoxycarbonyl, N-C₁₋₆ alkylcarbamoyl, N,N-di-(C₁₋₆alkyl)carbamoyl, C₂₋₆ alkanoyl, C₁₋₆ alkanoyloxy, C₁₋₆ alkanoylamino,N-(C₁₋₆ alkyl-C₂₋₆ alkanoylamino, N-C₁₋₆ alkylsulphamoyl, N,N-di-(C₁₋₆alkyl)sulphamoyl, C₁₋₆ alkanesulphonylamino and N-C₁₋₆ alkyl-C₁₋₆alkanesulphonylamino or with a C₁₋₃ alkylenedioxy group, or from a groupof the structure:—X³-Q⁴wherein X³ is a direct bond or is selected from O and N(R⁸), wherein R⁸is hydrogen or C₁₋₆ alkyl, and Q⁴ is aryl, aryl-C₁₋₆ alkyl, heteroaryl,heteroaryl-C₁₋₆ alkyl, heterocyclyl or heterocyclyl-C₁₋₆ alkyl, and anygroup optionally is substituted with 1 or 2 substituents, which may bethe same or different, selected from halogeno, trifluoromethyl, cyano,hydroxy, amino, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino and di-(C₁₋₆alkyl)amino,

and wherein any heterocyclyl group within a substituent on Q¹ optionallyis substituted with 1 or 2 oxo or thioxo substituents,

and wherein a single pair of adjacent carbon atoms in a C₂₋₆ alkylenechain within a Q¹ substituent is optionally separated by the insertionof a group selected from O, S, SO, SO₂, N(R⁹), CO, CH(OR⁹), CON(R⁹),N(R⁹)CO, SO₂N(R⁹) and N(R⁹)SO₂ wherein R⁹ is hydrogen or C₁₋₆ alkyl,

and wherein any CH₂ or CH₃ group within a group optionally issubstituted on each said CR₂ or CH₃ group with one or more halogen orC₁₋₆ alkyl substituents or a substituent selected from hydroxy, cyano,amino, carboxy, carbamoyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₆alkylsulphinyl, C₁₋₆ alkylsulphonyl, C₁₋₆ alkylamino, di-(C₁₋₆alkyl)amino, C₁₋₆ alkoxycarbonyl, N-(C₁₋₆ alkylcarbamoyl, N,N-di-(C₁₋₆alkyl)carbamoyl, C₁₋₆ alkanoyl, C₁₋₆ alkanoyloxy, C₁₋₆ alkanoylamino,N-(C₁₋₆ alkyl-C₁₋₆ alkanoylamino N-C₁₋₆alkylsulphamoyl, N,N-di-(C₁₋₆alkyl)sulphamoyl, C₁₋₆ alkanesulphonylamino and N-C₁₋₆ alkyl-C₁₋₆alkanesulphonylamino.

The compounds of structure (VII) can be made using organic synthesistechniques known to those skilled in the art, as well as by the methodsdescribed in International Publication No. WO 01/27089, which isincorporated herein by reference in its entirety (particularly at page3, line 7 to page 5, line 29). Further, specific examples of thesecompounds can be found in this publication.

In another embodiment, the JNK inhibitor has the following structure(VIII):

wherein:

R¹ is selected from C₁₋₆ alkyl (optionally substituted by one or twosubstituents independently selected from halo, amino, C₁₋₄ alkylamino,di-(C₁₋₄ alkyl)amino, hydroxy, cyano, C₁₋₄ alkoxy, C₁₋₄ alkoxycarbonyl,carbamoyl, —NHCO C₁₋₄ alkyl, trifluoromethyl, phenylthio, phenoxy,pyridyl, morpholino), benzyl, 2-phenylethyl, C₃₋₅ alkenyl (optionallysubstituted by up to three halo substituents, or by one trifluoromethylsubstituent, or one phenyl substituent), N-phthalimido-C₁₋₄ alkyl, C₃₋₅alkynyl (optionally substituted by one phenyl substituent) and C₃₋₆cycloalkyl-C₁₋₆ alkyl;

wherein any phenyl or benzyl group of R¹ is optionally substituted by upto three substituents independently selected from halogeno, hydroxy,nitro, amino, C₁₋₃ alkylamino, di-(C₁₋₃ alkyl)amino, cyano,trifluoromethyl, C₁₋₃ alkyl (optionally substituted by 1 or 2substituents independently selected from halogeno, cyano, amino, C₁₋₃alkylamino, di-(C₁₋₃ alkyl)amino, hydroxy and trifluoromethyl), C₁₋₃alkenyl (optionally substituted by up to three halo substituents, or byone trifluoromethyl substituent), C₁₋₃ alkynyl, C₁₋₃ alkoxy, —SH,—S—C₁₋₃ alkyl, carboxy, C₁₋₃ alkoxycarbonyl; Q₁ and Q₂ are independentlyselected from phenyl, naphthyl, indanyl and 1,2,3,4-tetrahydronaphthyl;

and one or both of Q₁ and Q₂ is substituted on any available carbon atomwith one substituent of the structure (VIIIa) and Q₂ may optionally besubstituted on any available carbon atom with further substituents ofthe structure (VIIIa):

(provided that when present in Q₁ the substituent of structure (VIIa) isnot adjacent to the —NH-link);

wherein:

X is CH₂, O, S, NH or NRx (wherein Rx is C₁₋₄ alkyl, optionallysubstituted by one substituent selected from halo, amino, cyano, C₁₋₄alkoxy or hydroxy);

Y is H or as defined for Z;

Z is OH, SH, NH₂, C₁₋₄ alkoxy, C₁₋₄ alkylthio, —NH C₁₋₄ alkyl, —N(C₁₋₄alkyl)₂, —NH—C₃₋₈ cycloalkyl, pyrrolidin-1-yl, piperidin-1-yl,piperazin-1-yl (optionally substituted in the 4-position by C₁₋₄ alkylor C₁₋₄ alkanoyl), morpholino or thiomorpholino;

n is 1, 2 or 3;

m is 1, 2 or 3;

and Q₁ and Q₂ may each optionally and independently be substituted onany available carbon atom with up to four substituents independentlyselected from halogeno, hydroxy, thio, nitro, carboxy, cyano, C₂₋₄alkenyl (optionally substituted by up to three halo substituents, or byone trifluoromethyl substituent), C₂₋₄ alkynyl, C₁₋₅ alkanoyl, C₁₋₄alkoxycarbonyl, C₁₋₆ alkyl, hydroxy-C₁₋₆ alkyl, fluoro-C₁₋₄ alkyl,amino-C₁₋₃ alkyl, C₂₋₄ alkanoyloxy-C₁₋₄-alkyl, C₁₋₄ alkoxy-C₁₋₃ alkyl,carboxy-C₁₋₄ alkyl, C₁₋₄ alkoxycarbonyl-C₁₋₄ alkyl, carbamoyl-C₁₋₄alkyl, N-C₁₋₄ alkylcarbamoyl-C₁₋₄ alkyl, N,N-di-(C₁₋₄alkyl)-carbamoyl-C₁₋₄ alkyl, pyrrolidin-1-yl-C₁₋₃ alkyl,piperidin-1-yl-C₁₋₃ alkyl, piperazin-1-yl-C₁₋₃ alkyl, morpholino-C₁₋₃alkyl, thiomorpholino-C₁₋₃ alkyl, piperazin-1-yl, morpholino,thiomorpholino, C₁₋₄ alkoxy, cyano-C₁₋₄ alkoxy, carbamoyl-C₁₋₄ alkoxy,N-C₁₋₄ alkylcarbamoyl-C₁₋₄ alkoxy, N,N-di-(C₁₋₄ alkyl)-carbamoyl C₁₋₄alkoxy 2-aminoethoxy, 2-C₁₋₄ alkylaminoethoxy, 2-di-(C₁₋₄alkyl)aminoethoxy, C₁₋₄ alkoxycarbonyl-C₁₋₄ alkoxy, halogeno-C₁₋₄alkoxy, 2-hydroxyethoxy, C₂₋₄ alkanoyloxy-C₂₋₄ alkoxy, 2-C₁₋₄alkoxyethoxy, carboxy-C₁₋₄ alkoxy, C₃₋₅ alkenyloxy, C₃₋₅ alkynyloxy,C₁₋₄ alkylthio, C₁₋₄ alkylsulphinyl, C₁₋₄ alkylsulphonyl, hydroxy-C₂₋₄alkylthio, hydroxy-C₂₋₄ alkylsulphinyl, hydroxy C₂₋₄ alkylsulphonyl,ureido (H₂N—CO—NH—), C₁₋₄ alkylNH—CO—NH—, di-(C₁₋₄ alkyl)-N—CO—NH—, C₁₋₄alkyNH—CO—N(C₁₋₄ alkyl), di-(C₁₋₄ alkyl)N—CO—N(C₁₋₄ alkyl)-, carbamoyl,N-(C₁₋₄ alkyl)carbamoyl, N,N-di-(C₁₋₄ alkyl)carbamoyl, amino, C₁₋₄alkylamino, di-(C₁₋₄ alkyl)amino, C₂₋₄ alkanoylamino,

and also independently, or where appropriate in addition to, the aboveoptional substituents, Q₁ and/or Q₂ may optionally be substituted on anyavailable carbon atom with up to two further substituents independentlyselected from C₃₋₈ cycloalkyl, phenyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkoxy,phenylthio, phenyl, naphthyl, benzoyl, phenoxy, benzimidazol-2-yl and a5- or 6-membered aromatic heterocycle (linked via a ring carbon atom andcontaining one to three heteroatoms independently selected from oxygen,sulphur and nitrogen); wherein said naphthyl, phenyl, benzoyl, 5- or6-membered aromatic heterocyclic substituents and the phenyl group insaid phenyl-C₁₋₄ alkyl, phenylthio, phenoxy and phenyl-C₁₋₄ alkoxysubstituents may optionally be substituted with up to five substituentsindependently selected from halogeno, C₁₋₄ alkyl and C₁₋₄ alkoxy.

The compounds of structure (VIII) can be made using organic synthesistechniques known to those skilled in the art, as well as by the methodsdescribed in International Publication No. WO 00/12468, which isincorporated herein by reference in its entirety (particularly at page2, line 10 to page 4, line 14). Further, specific examples of thesecompounds can be found in this publication.

In another embodiment, the JNK inhibitor has the following structure(IX):

wherein:

X is O, S or NR⁰, with R⁰ being H or an unsubstituted or substitutedC₁-C₆ alkyl;

G is an unsubstituted or substituted pyrimidinyl group;

R¹ is selected from the group comprising or consisting of hydrogen,unsubstituted or substituted C₁-C₆-alkoxy, unsubstituted or substitutedC₁-C₆-thioalkoxy, unsubstituted or substituted C₁-C₆-alkyl,unsubstituted or substituted C₂-C₆-alkenyl, unsubstituted or substitutedC₂-C₆-alkynyl, primary, secondary or tertiary amino groups, aminoacyl,aininocarbonyl, unsubstituted or substituted C₁-C₆ alkoxycarbonyl,unsubstituted or substituted aryl, unsubstituted or substitutedheteroaryl, carboxyl, cyano, halogen, hydroxy, nitro, sulfoxy, sulfonyl,sulfonamide, unsubstituted or substituted hydrazides;

R² is selected from the group comprising or consisting of hydrogen,unsubstituted or substituted C₁-C₆-alkyl, unsubstituted or substitutedC₂-C₆-alkenyl, unsubstituted or substituted C₂-C₆-alkynyl, unsubstitutedor substituted C₁-C₆-alkyl-aryl, unsubstituted or substituted aryl orheteroaryl, unsubstituted or substituted C₁-C₆-alkyl-heteroaryl,—C(O)—OR³, —C(O)—R³, —C(O)—NR³R^(3′), —(SO₂)R³, with

R³ and R^(3′)being independently selected from the group comprising orconsisting of hydrogen, unsubstituted or substituted C₁-C₆ alkyl,unsubstituted or substituted C₂-C₆ alkenyl, unsubstituted or substitutedC₂-C₆ alkynyl, unsubstituted or substituted aryl, unsubstituted orsubstituted heteroaryl, unsubstituted or substituted C₁-C₆-alkyl aryl,unsubstituted or substituted C₁-C₆-alkyl heteroaryl.

The compounds of structure (IX) can be made using organic synthesistechniques known to those skilled in the art, as well as by the methodsdescribed in European Patent Publication 1 110 957, filed Dec. 24, 1999which is incorporated herein by reference in its entirety (particularlyat page 19, line 52 to page 21, line 9). Further, specific examples ofthese compounds can be found in this publication.

In another embodiment, the JNK inhibitor has the following structure(X):

wherein:

Y is from O, NH, N(R), S, S(O) or S(O)₂.

X is from O, NH, or N(R).

R₁ and R₂ are each independently selected from H, a C₁-C₆ straight chainor branched alkyl or alkenyl group, optionally substituted with one tofour substituents, each of which is independently selected from NH₂,NHR, N(R)₂, NO₂, OH, OR, CF₃, halo, CN, CO₂H, CONH₂, CONHR, CON(R)₂,COR, SR, S(O)R, S(O)₂R, S(O)₂NH₂, S(O)₂NHR or R; a 5-7 membered aromaticor non-aromatic carbocyclic or heterocyclic ring, optionally substitutedwith one to four substituents, each of which is independently selectedfrom NH₂, NHR, N(R)₂, NO₂, OH, OR, CF₃, halo, CN, CO₂H, CONH₂, CONHR,CON(R)₂, COR, SR, S(O)R, S(O)₂R, S(O)₂NH₂, S(O)₂NHR or R; or a 9-10membered bicyclic aromatic or non-aromatic carbocyclic or heterocyclicring optionally substituted with one to four substituents, each of whichis independently selected from NH₂, NHR, N(R)₂, NO₂, OH, OR, CF₃, halo,CN, CO₂H, CONH₂, CONHR, CON(R)₂, COR, SR, S(O)R, S(O)₂R, S(O)₂NH₂,S(O)₂NH₂, S(O)₂NHR or R.

The compounds of structure (X) can be made using organic synthesistechniques known to those skilled in the art, as well as by the methodsdescribed in International Publication No. WO 00/75118, which isincorporated herein by reference in its entirety (particularly at page8, line 10 to page 11, line 26). Further, specific examples of thesecompounds can be found in this publication.

In another embodiment, the JNK inhibitor has the following structure(XI):

wherein:

X—Y-Z is selected from one of the following:

R¹ is H, CONH₂, T_((n))-R, or T_((n))-Ar²;

R is an aliphatic or substituted aliphatic group;

n is zero or one;

T is C(═O), CO₂, CONH, S(O)₂, S(O)₂NH, COCH₂, or CH₂;

each R² is independently selected from hydrogen, —R, —CHOR, —CH₂OH,—CH═O, —CH₂SR, —CH₂(O)₂R, —CH₂(C═O)R, —CH₂CO₂R, —CH₂CO₂H, —CH₂CN,—CH₂NHR, —CH₂N(R)₂, —CH═N—OR, —CH═NNHR, —CH═NN(R)₂, —CH═NNHCOR,—CH═NNHCO₂R, —CH═NNHSO₂R, -aryl, -substituted aryl, —CH₂(aryl),—CH₂(substituted aryl), —CH₂NH₂, —CH₂NHCOR, —CH₂NHCONHR, —CH₂NHCON(R)₂,—CH₂NRCOR, —CH₂NHCO₂R, —CH₂CONHR, —CH₂CON(R)₂, —CH₂SO₂NH₂,—CH₂(heterocyclyl), —CH₂ (substituted heterocyclyl), -(heterocyclyl), or-(substituted heterocyclyl);

each R³ is independently selected from hydrogen, R, COR, CO₂R, orS(O)₂R;

G is R or Ar¹;

Ar¹ is aryl, substituted aryl, aralkyl, substituted aralkyl,heterocyclyl, or substituted heterocyclyl, wherein Ar¹ is optionallyfused to a partially unsaturated or fully unsaturated five to sevenmembered ring containing zero to three heteroatoms;

Q-NH is

wherein the H of Q-NH is optionally replaced by R³;

A or N or CR³;

U is CR³, O, S, or NR³;

Ar² is aryl, substituted aryl, heterocyclyl or substituted heterocyclyl,wherein Ar² is optionally fused to a partially unsaturated or fullyunsaturated five to seven membered ring containing zero to threeheteroatoms; and

wherein each substitutable carbon atom is Ar², including the fused ringwhen present, is optionally and independently substituted by halo, R,OR, SR, OH, NO₂, CN, NH₂, NHR, N(R)₂, NHCOR, NHCONHR, NHCON(R)₂, NRCOR,NHCO₂R, CO₂R, CO₂H, COR, CONHR, CON(R)₂, S(O)₂R, SONH₂, S(O)R, SO₂NHR,or NHS(O)₂R, and wherein each saturated carbon in the fused ring isfurther optionally and independently substituted by ═O, ═S, ═NNHR,═NNR₂, ═N—OR, ═NNHCOR, ═NNHCO₂R, ═NNHSO₂R, ═NNHSO₂R, or ═NR;

wherein each substitutable nitrogen atom in Ar² is optionallysubstituted by R, COR, S(O)₂R, or CO₂R.

The compounds of structure (XI) can be made using organic synthesistechniques known to those skilled in the art, as well as by the methodsdescribed in International Publication No. WO 01/12621, which isincorporated herein by reference in its entirety (particularly at page8, line 10 to page 10, line 7). Further, specific examples of thesecompounds can be found in this publication.

In another embodiment, the JNK inhibitor has the following structure(XII) or (XIII):

wherein:

Y is —(CH₂)-Q₁; —(CO)-Q¹; —(CO)NH-Q₁; —(CO)—O-Q₁; —(SO₂)-Q₁ or—(SO₂)NH-Q₁;

Q₁ is a C₁-C₆ straight chain or branched alkyl or alkenyl group; a 5-7membered aromatic or non-aromatic carbocyclic or heterocyclic ring; or a9-14 membered bicyclic or tricyclic aromatic or non-aromatic carbocyclicor heterocyclic ring system, wherein said alkyl, alkenyl, ring or ringsystem is optionally substituted with one to four substituents, each ofwhich is independently selected from NH₂, NH—R, N(R)₂, NO₂, OH, OR, CF₃,halo, CN, CO₂H, C(O)—NH₂, C(O)—NH—R, C(O)—N(R)₂, C(O)—R, SR, S(O)—R,S(O)₂—R, S(O)₂—NH—R or —R, the heterocyclic ring system and heterocyclicring containing 1 to 4 heteroatoms, which are independently selectedfrom N, O, S, SO and SO₂;

W is N or C, when W is N, R₈ is a lone pair of electrons, when W is C,R₈ is R₇;

A₁ is N or CR¹;

A₂ is N or CR²;

A₃ is N or CR³;

A₄ is N or CR⁴;

provided that at least one of A_(1, A) ₂, A₃ and A⁴ must not be N;

R¹ is —NHR⁵, —OR⁵, —SR⁵, or —R⁵;

R², R³, and R⁴ are independently selected from —(CO)NH₂, —(CO)NHR,—(CO)N(R)₂, —NHR⁵, —NHCH₂R⁵, —OR⁵, —SR⁵, —R⁵, —NH(CO)—R⁶, —NH(CO)—NHR⁶,—NH(CO)—NH(CO)R⁶, —NH(CO)—OR⁶, —NH(SO₂)—R⁶, —NH(SO₂)—NH R⁶, —C(O)OH,—C(O)OR, —(CO)-Q₁, —(CO) NH-Q₁, —(CO) NR-Q₁, —(CO)—O-Q₁, —(SO₂)-Q₁ or—(SO₂)NH-Q₁;

R⁵ and R⁶ are each independently selected from H; N(R)₂, NHOH, NO₂,C(O)OR or halo; a C₁-C₆ straight chain or branched alkyl, alkenyl oralkynyl group; a 5-7 membered aromatic or non-aromatic carbocyclic orheterocyclic ring; or a 9-14 membered bicyclic or tricyclic aromatic ornon-aromatic carbocyclic or heterocyclic ring, wherein said alkyl,alkenyl, ring or ring system is optionally substituted with one to foursubstituents, each of which is independently selected from NH₂, NHR,NHC(O)OR, N(R)₂, NO₂, OH, OR, CF₃, halo, CN, Si(R)₃, CO₂H, COOR, CONH₂,CONHR, CON(R)₂, COR, SR, S(O)R, S(O)₂R, S(O)₂NHR or R;

R⁷ is H; a C₁-C₆ straight chain or branched alkyl or alkenyl group; a5-7 membered aromatic or non-aromatic carbocyclic or heterocyclic ring;or a 9-14 membered bicyclic or tricyclic aromatic or non-aromaticcarbocyclic or heterocyclic ring; wherein said alkyl, alkenyl, ring orring system is optionally substituted with one to four substituents,each of which is independently selected from NH₂, NHR, N(R)₂, NO₂, OH,OR, CF₃, halo, CN, CO₂H, CONH₂, CONHR, CON(R)₂, COR, SR, S(O)R, S(O)₂R,S(O)₂NHR or R;

R is a C₁-C₆ straight chain or branched alkyl or alkenyl group, a 5-7membered aromatic or non-aromatic carbocyclic or heterocyclic ring, or a9-10 membered bicyclic aromatic or non-aromatic carbocyclic orheterocyclic ring system; and

Z is CH or N.

The compounds of structure (XII) and structure (XIII) can be made usingorganic synthesis techniques known to those skilled in the art, as wellas by the methods described in International Publication No. WO00/64872, which is incorporated herein by reference in its entirety(particularly at page 9, line 1 to page, 106, line 2). Further, specificexamples of these compounds can be found in this publication.

In another embodiment, the JNK inhibitor has the following structure(XIV):

wherein:

Ar¹ and Ar2 are independently from each other aryl or heteroaryl,

X is O or S;

R¹ is hydrogen or a C₁-C₆-alkyl group, or R¹ forms a 5-6-memberedsaturated or unsaturated ring with Ar¹;

n is an integer from 0 to 5;

Y is an optionally substituted 4-12-membered saturated cyclic orbicyclic alkyl containing a nitrogen, which forms a bond with thesulfonyl group of formula XIV.

The compounds of structure (XIV) can be made using organic synthesistechniques known to those skilled in the art, as well as by the methodsdescribed in International Publication No. WO 01/23378, published Apr.5, 2001, which is incorporated herein by reference in its entirety(particularly at page 90, line 1 to page 91, line 1). Further, specificexamples of these compounds are found in said publication.

In another embodiment, the JNK inhibitor has the following structure(XV):

wherein:

Z is CH or N;

a is 1 or 2;

b is 1, 2 or 3;

c is 1, 2 or 3;

each R¹ is independently selected from groups of the formula:—(X)^(d)—(CH₂)_(e)—R⁵wherein:

d is 0 or 1;

e is 0 to 6;

X is O, NR⁶ or S(O)_(f) where f is 0, 1 or 2;

R⁵ is hydrogen, halogen, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₃₋₁₂cycloalkyl, heterocyclyl, aryl, heteroaryl, hydroxyl, cyano, nitro,trihalomethyl, NR⁷R⁸, C₆H₄NR⁷R⁸, C₆H₄(CH₂)NR⁷R⁸, C(O)R⁷, C(O)NR⁷R⁸,OC(O)R⁷, OC(O)NR⁷R⁸, CO₂R⁷, OCO₂R⁷, SO₂R⁷, SO₂NR⁷R⁸, C(═NR⁷)NR⁷R⁸,NR⁷(C═NR⁷)NR⁷R⁸, NHC(O)R⁷ or N(C₁₋₃alkyl)C(O)R⁷;

each R² is independently selected from hydrogen, cyano, halogen,trihalomethyl, OC₁₋₆alkyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,S(O)_(g)C₁₋₆alkyl where g is 0, 1 or 2, NC₁₋₆alkyl(C₁₋₆alkyl), hydroxylor nitro;

each R⁴ is independently selected from groups of the formula—(Y)_(d)—(CH₂)_(e)—R³wherein:

d is 0 or 1;

e is 0 to 6;

Y is O or S(O)_(f) where f is 0, 1 or 2;

R³ is hydrogen, halogen, C₁₋₆alkyl, C₂-alkenyl, C₂₋₆alkynyl,C₃₋₁₂cycloalkyl, heterocyclyl, aryl, heteroaryl, hydroxyl, cyano, nitro,trihalomethyl, phthalamido, C₆H₄NR⁷R⁸, C₆H₄(CH₂)NR⁷R⁸, C(O)R⁷,C(O)NR⁷R⁸, OC(O)R⁷, OC(O)NR⁷R⁸, CO₂R⁷, OCO₂R⁷, SO₂R⁷, SO₂NR⁷R⁸ orC(═NR⁷)NR⁷R⁸;

R⁶ is H, C₁₋₆alkyl, C₂₋₆alkenyl, aryl, heteroaryl, C₃₋₁₂cycloalkyl, orheterocyclyl;

R⁷ and R⁸ are each independently H, C₁₋₈alkyl, C₂₋₆alkenyl,SO₂C₁₋₆alkyl, (CH₂)_(m)—C₃₋₁₂cycloalkyl, (CH₂)_(m)-aryl,(CH₂)mheterocyclyl, (CH₂)mheteroaryl, wherein m=0, 1 or 2, or may,together with the nitrogen atom to which they are bound, form aheterocyclyl group; and

wherein any of said alkyl, alkenyl and alkynyl groups may be optionallysubstituted with up to three members selected from halogen, hydroxyl,oxo, cyano, NR⁷R⁸, C₁₋₆alkyl, OC₁₋₆alkyl, S(O)C₁₋₆alkyl, S(O)₂C₁₋₆alkyland SO₂NR⁷R⁸; and

wherein any of said cycloalkyl, heterocyclyl, aryl, and heteroarylgroups may be optionally substituted with substituents selected from agroup consisting of C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkylsulfenyl,C₁₋₆alkylsulfinyl, C₁₋₆alkylsulfonyl, hydroxy, oxo, mercapto, nitro,cyano, halogen, C₁₋₆perfluoroalkyl, amino optionally substituted byC₁₋₆alkyl, carbamoyl optionally substituted by C₁₋₆alkyl, NR⁷R⁸, carboxyand aminosulfonyl optionally substituted by C₁₋₆alkyl.

The compounds of structure (XV) can be made using organic synthesistechniques known to those skilled in the art, as well as by the methodsdescribed in International Publication No. WO 02/16359, published Feb.28, 2002, which is incorporated herein by reference in its entirety(particularly at page 163, line 1 to page 164, line 25). Further,specific examples of these compounds are found in said application andpublication.

In another embodiment, the JNK inhibitor is:

-   2-(4-Cyanophenyl)-4-(4-fluorophenyl)-5(4 pyridyl)-1H-imidazole;-   1-Methyl-2-(4-methoxyphenyl)-4-phenyl-5-(4-pyridyl)-imidazole;-   2-(4-Cyanophenyl)-1-methyl-4-phenyl-5(4-pyridyl)-imidazole;-   2-(4-Aminomethylphenyl)-1-methyl-4-phenyl-5-(4-pyridyl)-imidazole;-   4-[1-Methyl-4-phenyl-5(4-pyridyl)-imidazol-2-yl]benzoic acid, sodium    salt;-   2-(4-Acetamidomethyphenyl)-1-methyl-4-phenyl-5(4-pyridyl)imidazole;-   Methyl-4-[-methyl-4-phenyl-5-(4-pyridyl)imidazol-2-yl]benzoate;-   4-(4-Fluorophenyl)-N-1-hydroxy-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole;-   4-(4-Fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)-1H-imidazole;-   4-[4-(4-Fluorophenyl)-5-(4-pyridyl)-1H-imidazol-2-yl]benzoic acid;-   2-(4-Cyanophenyl)-4-(4-fluorophenyl)-1-N-hydroxy-5-(4-pyridyl)imidazole;-   2-(4-Aminomethylphenyl)-4-(4-fluorophenyl)-5-(4-pyridyl)-1H-imidazole;-   2-(4-Cyanophenyl)-4-(4-fluorophenyl)-N-1-hydroxy-5-(4-quinolyl)imidazole;-   2-(4-Cyanophenyl)-4-(4-fluoropbenyl)-5-(4-quinolyl)-1H-imidazole;-   2-(3,5-Dibromo-4-hydroxyphenyl)-4-(4-fluorophenyl)-5-(4-pyridyl)-1H-imidazole;-   Ethyl    4-[4-(4-Fluorophenyl)-5-(4-pyridyly]-1H-ijmidazol-2-yl]-benzoate;-   2-[3,5-Dimethyl-4-hydroxy    (phenyl)]-4-(4-fluorophenyl)-5-(4-pyridyl)-1H-imidazole;-   4-(4-Fluorophenyl-2-(2-hydroxyphenyl)5-(4-pyridyl)-1H-imidazole;-   4-(4-Fluorophenyl)-2-(4-methylthiophenyl)-5-(4-pyridyl)-1H-imidazole;-   Methyl    4-[4-(4-fluorophenyl)-5-(4-pyridyl)-1H-imidazol-2-yl]-benzoate;-   4-(4-Fluorophenyl)-2-(4-methylsulfonylphenyl)-5-(4-pyridyl)-1H-imidazole;-   4-(4-Fluorophenyl)-2-(4-methylsulfinylphenyl)5-(4-pyridyl)-1H-imidazole;-   N,N-Dimethyl-4-[4-(4-fluorophenyl-5-(4-pyridyl)-1H-imidazol-2-yl]-benzamine;-   2-[(4-N,N-Dimethyl)aminomethylphenyl]-4(4-fluorophenyl)-5-(4-pyridyl)-1H-imidazole;-   2-[4-(Dimethylamino)phenyl]-4(4fluorophenyl)-5-(4-pyridyl)-1H-imidazole;-   4-(4-Fluorophenyl)-2-phenyl-5-(4-pyridyl)-1H-imidazole;-   2-[4-(3-Dimethylaminopropoxy)phenyl]-4(4-fluorophenyl)-5-(4-pyridyl)-1H-imidazole;-   4-(4-Fluorophenyl)-2-(4-nitrophenyl)-5-(4-pyridyl)-1H-imidazole;-   N,N-Dimethyl-4-[2-(4-fluorophenyl)5-(4-pyridyl)-1H-imidazol-2-yl]-benzoyloxyacetamnide;-   2-(4-Aminophenyl)-4-(4-fluorophenyl)-5-(4-pyridyl)-1H-imidazole;-   4-(4-Fluorophenyl)-2-(4-methanesulfonamidophenyl)-5-(4-pyridyl)-1H-imidazole;-   4-[4-(4-Fluorophenyl)-5-(4-pyridyl)-1H-imidazol-2-yl]phenyl-sulfonamide;-   N′-Cyano-N-4-[4-(fluorophenyl)-5-(4-pyridyl)-1H-imidazol-2-yl]benzylguanidine;-   2-[4-(Methanesulfonamido)methytpheny]-4(4-fluorophenyl)-5-(4-pyridyl)-1H-imidazole;-   4-(4-Fluorophenyl)-2-(4-methoxyphenyl)-5(4 pyridyl)-1H-imidazole;-   2-(4-Amino-3-iodophenyl)-4-(4-fluorophenyl)-5-(4-pyridyl)-1H-imidazole;-   N-Benzyl-N-methyl-4-[4-(4-fluorophenyl-5-(4-pyridyl)-1H-imidazol-2-yl]benzamide;-   2-[4-(N-Benzyl-N-methyl)aminomethyphenyl]-4-(4-fluorophenyl)-5-(4-pyridyl)-1H-imidazole;-   4-(4-Fluorophenyl)-N-1-hydroxy-2-(4-methylthiophenyl)-5-(4-quinolyl)imidazole;-   4-(4-Fluorophenyl)-2-(4-methylthiophenyl)-5(4-quinolyl)-1H-imidazole;-   4-(4-Fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-quinolyl)-1H-imidazole;-   4-(3-Chlorophenyl)-2-(4-methytsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole;-   4-(3-Chlorophenyl    )-N-1-hydroxy-2-(4-methylthiophenyl)-5-(4-pyridyl)-1H-imidazole;-   4-(3-Chlorophenyl)-2-(4-methylthiophenyl)-5-(4-pyridyl)-1H-imidazole;-   4-(4-Fluorophenyl)-2-(4-formamidomethylphenyl)-5-(4-pyridyl)-1H-imidazole;-   4-[4-(4-Fluorophenyl)-5-(4-pyridyl)-1H-imidazol-2-yl]-benzohydroxamic    acid;-   O-Benzyl-4-[4-(4-Flurophenyl)-5-(4-pyridyl)-1H-imidazol-2-yl)-benzohydroxamic    acid;-   4-[4-(4-Fluorophenyl)-5-(4-pyridyl)-1H-imidazol-2-yl]benzamidoxime;-   N′-Methyl-N′-cyano-N-[4(4-fluorophenyl)-5-(4-pyridyl)-1H-imidazol-2-yl]-benzylguanidine;-   N-1-Hydroxy-4-(3-methoxyphenyl)-2-(4-methylthiophenyl)-5-(4-pyridyl)-1H-imidazole;-   4-(3-ethoxyphenyl)-2-(4-methylthiophenyl)-5-(4-pyridyl)imidazole;-   4-(3-Methoxyphenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole;-   Morpholino-4-[4-(4-fluorophenyl)-5-(4-pyridyl)-1H-imidazol-2-yl]benzamide;-   4-(4-Fluorophenyl)-5-[4-(2-methylpyridyl)-2-(4-methylthiophenyl)-1H-imidazole;-   4-(4-Fluorophenyl)-5-[4-(2-methylpyridyl)-2-(4-methylsulfinylphenyl)-1H-imidazole;-   4-(4-Fluorophenyl)-N-1-hydroxy-5-(4-pyrimidinyl)-imidazole;-   4-(4-Fluorophenyl)-2-(4-methylthiophenyl)-5-(4    pyrimidinyl)-1H-imidazole;-   4-(4-Fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyrimidinyl)-1H-imidazole;-   4-(4-Fluorophenyl)-2-(4-methylsulfonylphenyl)-5-(4-pyrimidinyl)-1H-imidazole;-   4-(4-Fluorophenyl)-2-(4-Morpholinomethylphenyl)-5-(4-pyridyl)-1H-imidazole;-   4-(4-Fluorophenyl)-2-(4-hydroxymethyl)-5-(4-pyridyl)-1H-imidazole;-   4-[4-(4-Fluorophenyl)-5-(4-pyridyl)-1H-imidazol-2-yl]-benzaldehyde;-   4-(2-Methoxyphenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole;-   N-1-Hydroxy-4-(2-methoxyphenyl)-2-(4-methylthiophenyl)-5-(4-pyridyl)imidazole;-   4-(2-Methoxyphenyl)-2-(4-methylthiophenyl)-5-(4-pyridyl)-1H-imidazole;-   3-[4-(4-Fluorophenyl)-5-(4-pyridyl)-1H-imidazol-2-yl]phenyl-5-methyl-4,5-dihydro-1,2,4-oxadiazole;-   3-[4-(4-Fluorophenyl)-5-(4-pyridyl)-1H-imidazol-2-yl]phenyl-5-methyl-1,2,4-oxadiazole;-   4-(3-Aminophenyl)-2-(4-methylthiophenyl)-5-(4-pyridyl)-1H-imidazole;-   N-1-Hydroxy-2-(4-methylthiophenyl)-4-(3-nitrophenyl)-5-(4-pyridyl)imidazole;-   2-(4-Methylthiophenyl)-4-(3-nitrophenyl)-5-(4-pyridyl)-1H-imidazole;-   4-(3-Methanesulfonamidophenyl)-2-(4-methylthiophenyl)-5-(4-pyridyl)-1H-imidazole;-   3-[4-(4-Fluorophenyl)-5-(4-pyridyl)-1H-imidazol-2-yl]phenyl-1,2,4-oxadiazol-5(4H)-one;-   4-(3-Acetamidophenyl)-2-(4-methylthiophenyl)-5-(4-pyridyl)-1H-imidazole;-   4-(4-Fluorophenyl)-1-N-hydroxy-5-[4-(2-methylpyridyl)]-2-(4-methylthiophenyl)-imidazole-   3-[4-(4-Fluorophenyl)-5-(4-pyridyl)-1H-imidazol-2-yl]-phenyl-5,5-dimethyl-4,5-dihydro-1,2,4-oxadiazote;-   N-Hydroxy-N-1-[4-[4-(4-fluorophenyl)-5-(4-pyridyl)-1H-imidazol-2-yl]phenyl]-ethyl]urea;-   N-Hydroxy-N-[4-[4-(4-fluorophenyl)-5-(4-pyridyl)-1H-imidazol-2-yl-phenyl]-methyl    urea;-   4-(3-Methylthiophenyl)-2-(4-morpholinomethylphenyl)-5-(4-pyridyl)-1H-imidazole;-   4-(3-Methylsulfinylphenyl)-2-(4-morpholinomethylphenyl)-5-(4-pyridyl)-1H-imidazole;-   4-(3-Methanesulfonamidophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole-2-(4-Ethylthiophenyl)-4(4-fluorophenyl)-5-(4-pyridyl)-1H-imidazole;-   4-(4-Fluorophenyl)-2-[(4-(4-methyl-1-piperzinyl)-sulfonyl-phenyl]-5-(4-pyridyl)    1H-imidazole;-   4-(4-Fluorophenyl)-2-[4-(N-methylmethanesulfonamido)-methylphenyl]-5-(4-pyridyl)-1H-imidazole;-   Diethyl-[1-methyl-4-phenyl-5-(4-pyridyl)-imidazol-2-yl]-methoxy    methylphosphonate;-   4-(4-Fluorophenyl)-2-(4-methylthiophenyl)-5-(4-pyridyl)-1H-imidazole;-   4-(4-Fluorophenyl)-2-(3-methylthiophenyl)-5-(4-pyridyl)-1H-imidazole;-   4-(4-Fluorophenyl)-2-(3-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole;-   4-(4-Fluorophenyl)-2-(4-methoxyphenyl)-5-(4-pyridyl)imidazole;-   4-(4-Fluorophenyl)-2-(4-methylsulfinylphenyl)-1-(N-morpholinopropyl)-5-(4-pyridyl)-imidazole;-   4-(4-Fluorophenyl)-2-(4-methylthiophenyl)-1-(N-morpholinopropyl)-5-(4-pyridyl)-imidazole;-   4-(4-Fluorophenyl)-2-(4-methylsulfonylphenyl)-1-(N-morpholinopropyl)-5-(4-pyridyl)imidazole;-   4-(4-Fluorophenyl)-1-(methylthio-1-propyl)-2-([4-N-morpholinomethyl]phenyl)-5-(4-pyridyl)imidazole;-   4-(4-Fluorophenyl)-1-(methylsulfinyl-1-propyl)-2-([4N-morpholinomethyl]phenyl)-5-(4-pyridyl)imidazole;    and-   4-(4-Fluorophenyl)-1-(methylsulfonyl-1-propyl)-2-([4-N-morpholinomethyl]phenyl)-5-(4-pyridyl)imidazole.

These compounds can be made using organic synthesis techniques known tothose skilled in the art, as well as by the methods described in U.S.Pat. No. 6,288,089, issued Sep. 11, 2001, which is incorporated hereinby reference in its entirety. Further, specific examples of thesecompounds are found in the patent.

In another embodiment, the JNK inhibitor has the following structure(XVI):

or pharmaceutically acceptable in vivo hydrolyzable esters, analogs,hydrolysis products, metabolites, salts, solvates, hydrates, clathrates,polymorphs, stereoisomers, derivatives and precursors thereof, wherein:

A is aryl or heteroaryl, each of which optionally substituted by one ormore —OR⁴, —COR⁴, —COOR⁴, —CONR⁶R⁷, —NR⁶R⁷, —CN, —NO₂, —SO₂R⁴,—SO₂NR⁶R⁷, halogen, perfluoroalkyl, lower alkyl, lower alkyl substitutedby (a), halogen, cycloalkyl, and/or heterocycle; cycloalkyl orcycloalkyl substituted by (a), halogen, lower alkyl, and/or heterocycle;heterocycle or heterocycle substituted by (a), halogen, lower alkyl,and/or cyoloalkyl;

-   where (a) is —OR⁴, —NR⁶R⁷, —COR⁴, —COOR⁴, —OCOR⁴, —CONR⁵R⁷, —CN,    —NO₂, —SO₂R⁴, or —SO₂NR⁶R⁷;-   R² is hydrogen, —OR⁴, —COOR⁴, —CONR⁶R⁷, —NR⁶R⁷, halogen, —NO₂, —CN,    —SO₂NR⁶R⁷, —SO₂R⁴ perfluoroalkyl, lower alkyl, or lower alkyl    substituted by —OR⁸, NR⁶R⁷, —COR⁴, —COOR⁴, and/or —CONR⁶R⁷;

R³ is hydrogen, —OR⁴, —COR⁴, —COOR⁴, —CONR⁶R⁷, halogen, —CN, —NR⁶R⁷,perfluoroalkyl, lower alkyl, or lower alkyl substituted by —OR⁸ and/or—NR⁶R⁷;

R⁴ is hydrogen, lower alkyl or lower alkyl substituted by (b),cycloalkyl and/or heterocycle; cycloalkyl or cyoloalkyl substituted (b),lower alkyl and/or heterocycle; heterocycle or heterocycle substitutedby (b), lower alkyl and/cr cycloalkyl; where (b) is —OR⁵, —COOR⁸, —COR⁸,—CONR⁸R⁹, —NR⁶R⁷, —CN, —NO₂, —SO₂R⁸, or —SO₂NR⁸R⁹;

R⁵ is hydrogen, —COR⁸, —CONR⁸R⁹, lower alkyl or lower alkyl substitutedby —OR⁹, —NR⁹R¹⁰, —N(OCR⁹)R¹⁰, —COR⁸, —CONR⁹R¹⁰, and/or —COOR⁸;

R⁶ and R⁷ are each independently hydrogen, —COR⁸, —COOR⁸, —CONR⁸R⁹,—SO₂R⁸, —SO₂NR⁸R⁹, lower alkyl or lower alkyl substituted by cycloalkyl(or cycloalkyl substituted by (c), lower alkyl and/or heterocycle),heterocycle (or heterocycle substituted by (c), lower alkyl and/orcycloalkyl), aryl (or aryl substituted by (c), lower alkyl, cycloalkyland/or heterocycle), or heteroaryl (or heteroaryl substituted by (c),lower alkyl, cyoloalkyl and/or heterocycle); or

R⁶ and R⁷ are each independently cycloalkyl or cycloalkyl substituted by(c), lower alkyl and/or heterocycle; heterocycle (or heterocyclesubstituted by (c), lower alkyl and/or cycloalkyl), aryl (or arylsubstituted by (c), lower alkyl, cycloalkyl and/or heterooycle),orheteroaryl (or heteroaryl substituted by (c), lower alkyl, cycloalkyland/or heterocycle); where (c) is —OR⁵, —COOR⁸, —COR⁸, —CONR⁸R⁹, —CN,—NO₂, —SO₂R⁸, —SO₂NR⁸R⁹, —NR⁸R⁹;

or alternatively, —NR⁶R⁷ forms a ring having 3 to 7 atoms, said ringoptionally including one or more additional heteroatoms and beingoptionally substituted by one or more of lower alkyl, —OR⁵, —COR⁸,—COOR⁸, CONR⁸R⁹, and —NR⁵R⁹;

R⁸ is hydrogen, lower alkyl (or lower alkyl substituted by cycloalkyl,heterocycle, aryl, heteroaryl, —OR⁹, —NR⁹R¹⁰, and/or —N(COR⁹)R¹⁰), aryl(or aryl substituted by (d), lower alkyl, cycloalkyl, heterocycle,halogen and/or —SO₂F), heteroaryl (or heteroaryl substituted by (d),lower alkyl, cycloalkyl, heterocycle, halogen and/or —SO₂F), cycloalkyl(or cycloalkyl substituted by (d), lower alkyl, heterocycle and/oraryl), or heterocycle (or heterocycle substituted by (d), lower alkyl,cyoloalkyl and/or aryl); where (d) is —OR⁹, —COOR⁹, —COR⁹, —CONR¹⁰R⁹,—NR¹⁰R⁹, —CN, —NO₂, —SO₂R⁹, or —SO₂N¹⁰R⁹;

R⁹ and R¹⁰ are each independently hydrogen, lower alkyl or aryl; and Xis ═N— or ═CH—.

The compounds of structure (XVI) can be made using organic synthesistechniques known to those skilled in the art, as well as by the methodsdescribed in U.S. Pat. No. 6,307,056, issued Oct. 23, 2001, which isincorporated herein by reference in its entirety (particularly at column63, line 29 to column 66, line 12). Further, specific examples of thesecompounds are found in the patent.

In another embodiment, the JNK inhibitor has the following structure(XVII):

wherein:

R¹ and R² are independently selected from the group consisting of:hydrogen, —OR⁴, —COR⁴, —COOR⁴, —CONR⁵R⁶, —NR⁵R⁶, lower alkyl which maybe substituted by a member of the group (a) consisting of —OR⁴, —NR⁵R⁶,halogen, —COR⁴, —COOR⁴, —OCOR⁴, —CONR⁵R⁶, —CN, —SO₂R⁴, —SO₂NR⁵R⁶; or bycycloalkyl, heterocycle, aryl, and heteroaryl, wherein the cycloalkyland heterocycle each may be substituted by the group R¹¹ and the aryland heteroaryl each may be substituted by the group R¹²;

cycloalkyl which may be substituted by a member of the group (a) adefined earlier, or by lower alkyl, heterocycle, aryl, and heteroaryl,wherein the lower alkyl and heterocycle each may be substituted by thegroup R¹¹ and the aryl and heteroaryl each may be substituted by thegroup R¹²;

heterocycle which may be substituted by a member of the group (a) asdefined earlier, or by lower alkyl, cycloalkyl, aryl, and heteroaryl,wherein the lower alkyl and cycloalkyl each may be substituted by thegroup R¹¹ and the aryl and heteroaryl each maybe optionally substitutedby the group R¹²;

aryl which maybe substituted by a member of the group (b) consisting of—OR⁴, —NR⁵R⁶, halogen, —NO₂, perfluoroalkyl, —COR⁴, —COOR⁴, —OCOR⁴,—CONR⁵R⁶, —CN, —SO₂R⁴, —SO₂NR⁵R⁶; or by lower alkyl, cycloalkyl,heterocycle, aryl, and heteroaryl, and wherein the lower alkyl,cycloalkyl and heterocycle each may be substituted by the group R¹¹ andthe aryl and heteroaryl each maybe substituted by the group R¹²heteroaryl, which may be substituted by a member of the group (b) asdefined earlier, or by lower alkyl, cycloalkyl, heterocycle, aryl, andheteroaryl and wherein the lower alkyl, cycloalkyl and heterocycle eachmay be optionally substituted by the group R¹¹ and the aryl andheteroaryl each maybe substituted by the group R¹², or alternatively, R¹and R² can form a ring having 5-7 atoms, said ring optionally includingone or more heteroatoms and being optionally substituted by a member ofthe group consisting of —OR⁸, —COR⁷, —COOR⁷, —OCOR⁴, —CONR⁷R⁹, —NR⁸R⁹,or lower alkyl which may be substitute by the group R¹²;

R³ is hydrogen, —OR⁴, —COR⁴, —COOR⁴, —OCOR⁴, —CONR⁵R⁶, halogen, —CN,perfluoroalkyl —NR⁵R⁶, or lower alkyl which may be substituted by —OR⁴,—OCOR⁴, or —NR⁵R⁶;

R⁴ is hydrogen, lower alkyl which may be substituted by a member of thegroup(c) consisting of —OR⁸, —COOR⁷, —COR⁷, —CONR⁵R⁶, —NR⁵R⁶, —SO₂R⁷,—SO₂NR⁵R⁶ or by cycloalkyl, heterocycle, aryl, and heteroaryl, andwherein the cycloalkyl and heterocycle each may be substituted by thegroup R¹¹ and the aryl and heteroaryl each may be substituted by thegroup R¹²,

cycloalkyl which may be substituted by a member of the group (c) or bylower alkyl, heterocycle, aryl, and heteroaryl, and wherein the loweralkyl and heterocycle each may be substituted by the group R¹¹ and thearyl and heteroaryl each may be substituted by the group R¹²,

heterocycle which maybe substituted by a member of the group (c) or bycycloalkyl, lower alkyl, aryl, and heteroaryl, and wherein thecycloalkyl and lower alkyl each may be substituted by the group R¹¹ andthe aryl and heteroaryl each may be substituted by the group R¹²,

aryl which maybe substituted by a member of the group (d) consisting of—OR⁸, —COOR⁷, —COR⁷, —CONR⁵R⁶, —NR⁵R⁶, —NO₂, halogen, perfiuoroalkyl,—SO₂R⁷, —SO₂NR⁵R⁶ or by lower alkyl, cycloalkyl, heterocycle, aryl, andheteroaryl, and wherein the lower alkyl, cycloalkyl and heterocycle eachmay be substituted by the group R¹¹ and the aryl and heteroaryl each maybe substituted by the group R¹², and

heteroaryl which may be substituted by a member of the group (d) or bycycloalkyl, lower alkyl, heterocycle, aryl, and heteroaryl, and whereinthe lower alkvl, cycloalkyl and heterocycle each may be substituted bythe group R¹¹ and the aryl and heteroaryl each maybe substituted by thegroup R¹²;

R⁵ and R⁸ are each independently hydrogen, —COR⁷, —COOR⁷, —CONR⁷R⁹,lower alkyl which may be substituted by a member of the group (e)consisting of —OR⁸, —COOR⁷, —COR⁷, —CONR⁷R⁸, —NR⁷R⁸, —SO₂R⁷, —SO₂NR⁷R⁵;or by cycloalkyl, heterocycle, aryl, and heteroaryl, and wherein thecycloalkyl and heterocycle each may be substituted by the group R¹¹ andthe aryl and heteroaryl each may be substituted by the group R²,

cycloalkyl which may be substituted by a member of the group (e) asdefined earlier, or by lower alkyl, heterocycle, aryl, and heteroaryl,and wherein the lower alkyl and heterocycle each maybe substituted bythe group R¹¹ and the aryl and heteroaryl each may be substituted by thegroup R¹²,

heterocycle which may be substituted by a member of the group (e) asdefined earlier, or by cycloalkyl, lower alkyl, aryl, and heteroaryl,and wherein the cycloalkyl and lower alkyl each may be substituted bythe group R¹¹ and the aryl and heteroaryl each maybe substituted by thegroup R¹²,

aryl which may be substituted by a member of the group (f) consisting ofOR⁸, —COOR⁷, —COR⁷, —CONR⁷R⁸, —NR⁷R⁸, —NO₂, halogen, perfluoroalkyl,—SO₂R⁷, —SO₂NR⁷R⁸ or by lower alkyl, cycloalkyl, heterocycle, aryl, andheteroaryl, and wherein the lower alkyl, cycloalkyl and heterocycle eachmay be substituted by the group R¹¹ and the aryl and heteroaryl eachmaybe substituted by the group R¹², and

heteroaryl which may be substituted by a member of the group (f) asdefined earlier, or by lower alkyl, cycloalkyl, heterocycle, aryl, andheteroaryl, and wherein the lower alkyl, cycloalkyl and heterocycle eachmay be substituted by the group R¹¹ and the aryl and heteroaryl each maybe substituted by the group R¹² or alternatively, —NR⁵R⁶ can form a ringhaving 3 to 7 atoms, said ring optionally including one or moreadditional hetero atoms and being optionally substituted by lower alkyl,—OR⁸, —COR⁷, —COOR⁷, —CONR⁸R⁹, or —NR⁸R⁹;

R⁷ is hydrogen or lower alkyl which may be substituted by a member ofthe group consisting of cycloalkyl, heterocycle, aryl, heteroaryl, —OR⁹,or —NR⁸R⁹;

R⁸ is hydrogen, —COR⁹, —CONR¹⁰R⁹, or lower alkyl which may besubstituted by R¹¹;

R⁹ and R¹⁰ are each independently hydrogen or lower alkyl;

R¹¹ is —OR⁹, —COR⁹, —COOR⁹, —OCOR⁹, —CONR⁹R¹⁰, —NR⁹R1⁰, —N(COR⁹)R¹⁰,—SO₂R⁹, or —SO₂NR⁸R¹⁰;

R¹² is —OR⁹, —COR⁹, —COOR⁹, —OCOR⁹, —CONR⁹R¹⁰, —NR⁹R¹⁰, —N(COR⁹)R¹⁰,—SO₂R⁹, —SO₂NR⁹R¹⁰, halogen, —CN, —NO₂, or perfluoroalkyl; and

X is —N— or —C—.

The compounds of structure (XVII) can be made using organic synthesistechniques known to those skilled in the art, as well as by the methodsdescribed in International Publication No. WO 00/35921, published Jun.22, 2000, which is incorporated herein by reference in its entirety(particularly at page 23, line 5 to page 26, line 14). Further, specificexamples of these compounds are found in this publication.

In another embodiment, the JNK inhibitor has the following structure(XVIII):

wherein:

R₁ is —F, —Cl, —Br, —OH, —SH, —NH₂, or —CH₃;

R₂ is —F, —Cl, —Br, —OH, —SH, —NH₂, or —CH₃;

R₃ is —H, —F, —Cl, —Br, —OH, —SH, —NH₂, —CH₃, —OCH₃, or —CH₂CH₃;

R⁴ is —C₁₋₄alkyl optionally substituted with a —C₃₋₇cycloalkyl;

R₅ is —C₁₋₄alkyl or —C₃₋₇cycloalkyl, wherein the —C₁₋₄alkyl isoptionally substituted with a phenyl;

X is a bond or an alkyl bridge having 1-3 carbons;

Y is —NH— or —NH2⁺—; and

HETCy is a 4 to 10 membered non-aromatic heterocycle containing at leastone N atom, optionally containing 1-2 additional N atoms and 0-10 or Satom, and optionally substituted with —C₁₋₄alkyl or —C(O)—O—CH₂ phenyl.

The compounds of structure (XVIII) can be made using organic synthesistechniques known to those skilled in the art, as well as by the methodsdescribed in International Publication No. WO 01/91749, published Dec.6, 2001, which is incorporated herein by reference in its entirety(particularly at page 29, lines 1-22). Further, specific examples ofthese compounds are found in this publication.

In another embodiment, the JNK inhibitor has the following structure(XIX):

wherein:

Ht is a heterocyclic ring selected from pyrazol-3-yl,[1,2,4]triazol-3-yl, [1,2,3]triazol-4-yl, or tetrazol-5-yl, saidpyrazol-3-yl having R³ and QR⁴ substituents, and said[1,2,4]triazol-3-yl or [1,2,3]triazol-4-yl substituted by either R³ orQR⁴;

R¹ is selected from R, halogen, N(R⁸)₂, OR, NRCOR, NRCON(R⁸)₂, CON(R⁸)₂,SO₂R, NRSO₂R, or SO₂N(R⁸)₂;

T is selected from a valence bond or a linker group;

each R is independently selected from hydrogen or an optionallysubstituted aliphatic group having one to six carbons;

R² is selected from hydrogen, CN, halogen, aryl, aralkyl, heteroaryl,heterocyclyl, an optionally substituted acyclic aliphatic chain grouphaving one to six carbons, or an optionally substituted cyclic aliphaticgroup having four to ten carbons;

R³ is selected from R, OH, OR, N(R⁸)₂, halogen, or CN;

Q is a valence bond, J, or an optionally substituted C₁₋₆ alkylidenechain wherein up to two nonadjacent carbons of the alkylidene chain areeach optionally and independently replaced by J;

J is selected from —C(═O)—, —CO₂—, —C(O)C(O)—, —NRCONR⁸—, —N(R)N(R⁸)—,—C(═O)NR⁸—, —NRC(═O)—, —O—, —S—, —SO—, —SO₂—, —N(R)O—, —ON(R⁸)—,—OC(═O)N(R⁸)—, —N(R)COO—, —SO₂N(R⁸)—, —N(R)SO₂—, or —NC(R⁸);

R⁴ is selected from —R⁸, —R⁵, —NH₂, —NHR⁵, —N(R⁵)₂, or—NR⁵(CH₂)_(y)N(R⁵)₂;

each R⁵ is independently selected from R⁶, R⁷, —(CH₂)_(y)CH(R⁶)(R⁷),—(CH₂)yR⁶, —(CH₂)_(y)CH(R⁶)₂, —(CH₂)_(y)CH(R⁷)₂, or —(CH₂)_(y)R⁷;

y is 0-6;

each R⁶ is an optionally substituted group independently selected froman aliphatic, aryl, aralkyl, aralkoxy, heteroaryl, heteroarylalkyl,heteroarylalkoxy, heterocyclyl, heterocyclylalkyl, orheterocyclylalkoxy, group;

each R⁷ is independently selected from an optionally substitutedaliphatic, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, or alkoxycarbonyl;

each R⁸ is independently selected from R, or two R⁸ on the same nitrogenatom are taken together with the nitrogen to form a four to eightmembered, saturated or unsaturated heterocyclic ring having one to threeheteroatoms;

and each substitutable ring nitrogen is optionally substituted by R,NR₂, COR, CO₂(C₁-C₆ optionally substituted alkyl), SO₂(C₂-C₆ optionallysubstituted alkyl), CONR₂, and SO₂NR₂ provided that QR⁴ is other thanCON(CH₃)₂ when R¹ and R³ are each hydrogen and when TR² is anunsubstituted phenyl ring attached at the 4-position of the pyrazolering.

The compounds of structure (XIX) can be made using organic synthesistechniques known to those skilled in the art, as well as by the methodsdescribed in International Publication No. WO 01/56993, published Aug.9, 2001, which is incorporated herein by reference in its entirety(particularly in at page 43 to page 45). Further, specific examples ofthese compounds are found in this publication.

In another embodiment, the JNK inhibitor has the following structure(XX):

The compound of structure (XX) can be made using organic synthesistechniques known to those skilled in the art, as well as by the methodsdescribed in International Publication No. WO 01/58448, published Aug.16, 2001, which is incorporated herein by reference in its entirety(particularly in at page 39).

If the stereochemistry of a structure or a portion of a structure is notindicated with, for example, bold or dashed lines, the structure orportion of the structure is to be interpreted as encompassing allstereoisomers of it.

4.1.1 Patient Population

The invention provides methods for treating, preventing, and managingcancer by administrating to a patient a therapeutically orprophylactically effective amount of a JNK inhibitor in combination withone or more other therapeutic agents, or a pharmaceutical compositioncomprising a JNK inhibitor. The patient is preferably a mammal such asnon-primate (e.g., cows, pigs, horses, cats, dogs, rats etc.) and aprimate (e.g., monkey such as a cynomolgous monkey and a human). In apreferred embodiment, the patient is a human.

The invention encompasses methods for treating patients on any othertreatment usefull for the prevention or treatment of cancer. Using themethods of the invention, patients can be treated for the prevention,treatment or management of cancer, including, but not limited to,primary cancers, neoplasms, solid and blood born tumors, metastases, orany disease or disorder characterized by uncontrolled cell growth. Themethods and compositions of the invention can be used with one or moreconventional or experimental therapies that are used to prevent, manageor treat cancer.

Specific examples of cancers that can be treated by the methodsencompassed by the invention include, but are not limited to, cancer ofthe head, neck, eye, mouth, throat, esophagus, chest, bone, lung, colon,rectum, stomach, prostate, breast, ovaries, kidney, liver, pancreas, andbrain. In preferred embodiments, the cancer is breast cancer, coloncancer, prostate cancer, multiple myeloma, melanoma, lung cancer orovarian cancer. Additional cancers are listed by example and not bylimitation in the following section 4.1.1.1.

The methods and compositions of the invention comprise theadministration of a JNK inhibitor in combination with one or more othertherapeutic agents other than a JNK inhibitor to patients suffering fromor expected to suffer from cancer. As used herein, cancer refers toprimary or metastatic cancers. Such patients may or may not have beenpreviously treated for cancer. The methods and compositions of theinvention may be used as a first line or second line cancer treatment.The invention also comprises the treatment of a patient having cancerand immunosuppressed by reason of having previously undergone othercancer therapies. Included by the invention is also the treatment ofpatients undergoing other cancer therapies and the methods andcompositions of the invention can be used before any adverse effects orintolerance occurs. The invention also encompasses methods foradministering a JNK inhibitor to treat or ameliorate symptoms inrefractory patients. In a certain embodiment, that a cancer isrefractory to a therapy means that at least some significant portion ofthe cancer cells are not killed or their cell division arrested. Inanother embodiment, the cancer is refractory against currently usedchemotherapeutic agents. In another embodiment, the cancer is refractoryto multi-drug therapies. In another embodiment, the cancer is refractoryagainst tamoxifen. In another embodiment, the cancer isandrogen-independent. The determination of whether the cancer cells arerefractory can be made either in vivo or in vitro by any method known inthe art for assaying the effectiveness of treatment on cancer cells,using the art-accepted meanings of “refractory” in such a context. Invarious embodiments, a cancer is refractory where the number of cancercells has not been significantly reduced, or has increased. Theinvention also encompasses methods for administering a JNK inhibitor toprevent the onset or recurrence of cancer in patients predisposed tohaving cancer.

In alternate embodiments, the invention provides methods for treatingpatients cancer by administering a JNK inhibitor in combination with anyother treatment or to patients who have proven refractory to othertreatments but are no longer on these treatments. In certainembodiments, the patients being treated by the methods of the inventionare patients already being treated with chemotherapy, radiation therapy,hormonal therapy, or biological therapy/immunotherapy. Among thesepatients are refractory patients and those with cancer despite treatmentwith existing cancer therapies. In other embodiments, the patients havebeen treated and have no disease activity and a JNK inhibitor isadministered to prevent the recurrence of cancer.

In preferred embodiments, the existing treatment is chemotherapy. Inparticular embodiments, the existing treatment includes administrationof chemotherapies including, but not limited to methotrexate,mercaptopurine, thioguanine, hydroxyurea, cytarabine, cyclophosphamide,ifosfamide, nitrosoureas, cisplatin, carboplatin, mitomycin,dacarbazine, procarbizine, etoposides, campathecins, bleomycin,doxorubicin, idarubicin, daunorubicin, dactinomycin, plicamycin,mitoxantrone, asparaginase, vinblastine, vincristine, vinorelbine,paclitaxel, docetaxel, cetuximab (Erbitux™), thalidomide, any SelCid™ orIMiD™ compounds, in particular CC-4047 (Actimid™) and CC-5013(Revimid™). Among these patients are patients treated with radiationtherapy, hormonal therapy and/or biological therapy/immunotherapy. Alsoamong these patients are those who have undergone surgery for thetreatment of cancer.

Alternatively, the invention also encompasses methods for treatingpatients having radiation therapy. Among these patients are patientstreated with chemotherapy, hormonal therapy and/or biologicaltherapy/immunotherapy. Also among these patients are those who haveundergone surgery for the treatment of cancer.

In other embodiments, the invention encompasses methods for treatingpatients having hormonal therapy and/or biologicaltherapy/immunotherapy. Among these patients are patients treated withchemotherapy and/or radiation therapy. Also among these patients arethose who have undergone surgery for the treatment of cancer.

Additionally, the invention also provides methods of treatment of canceras an alternative to chemotherapy, radiation therapy, hormonal therapy,and/or biological therapy/immunotherapy where the therapy has proven ormay prove too toxic, i.e., results in unacceptable or unbearable sideeffects, for the patient being treated. The patient being treated withthe methods of the invention may, optionally, be treated with othercancer treatments such as surgery, chemotherapy, radiation therapy,hormonal therapy or biological therapy, depending on which treatment wasfound to be unacceptable or unbearable.

In other embodiments, the invention provides administration of a JNKinhibitor without any other cancer therapies for the treatment ofcancer, but who have proved refractory to such treatments. In specificembodiments, patients refractory to other cancer therapies areadministered a JNK inhibitor in the absence of cancer therapies.

4.1.1.1 Cancers

Cancers and related disorders that can be treated or prevented bymethods and compositions of the present invention include but are notlimited to the following: Leukemias such as but not limited to, acuteleukemia, acute lymphocytic leukemia, acute myelocytic leukemias such asmyeloblastic, promyelocytic, myelomonocytic, monocytic, erythroleukemialeukemias and myelodysplastic syndrome, chronic leukemias such as butnot limited to, chronic myelocytic (granulocytic) leukemia, chroniclymphocytic leukemia, hairy cell leukemia; polycythemia vera; lymphomassuch as but not limited to Hodgkin's disease, non-Hodgkin's disease;multiple myelomas such as but not limited to smoldering multiplemyeloma, nonsecretory myeloma, osteosclerotic myeloma, plasma cellleukemia, solitary plasmacytoma and extramedullary plasmacytoma;Waldenström's macroglobulinemia; monoclonal gammopathy of undeterminedsignificance; benign monoclonal gammopathy; heavy chain disease; boneand connective tissue sarcomas such as but not limited to bone sarcoma,osteosarcoma, chondrosarcoma, Ewing's sarcoma, malignant giant celltumor, fibrosarcoma of bone, chordoma, periosteal sarcoma, soft-tissuesarcomas, angiosarcoma (hemangiosarcoma), fibrosarcoma, Kaposi'ssarcoma, leiomyosarcoma, liposarcoma, lymphangiosarcoma, metastaticcancers, neurilemmoma, rhabdomyosarcoma, synovial sarcoma; brain tumorssuch as but not limited to, glioma, astrocytoma, brain stem glioma,ependymoma, oligodendroglioma, nonglial tumor, acoustic neurinoma,craniopharyngioma, medulloblastoma, meningioma, pineocytoma,pineoblastoma, primary brain lymphoma; breast cancer, including, but notlimited to, adenocarcinoma, lobular (small cell) carcinoma, intraductalcarcinoma, medullary breast cancer, mucinous breast cancer, tubularbreast cancer, papillary breast cancer, primary cancers, Paget'sdisease, and inflammatory breast cancer; adrenal cancer such as but notlimited to pheochromocytom and adrenocortical carcinoma; thyroid cancersuch as but not limited to papillary or follicular thyroid cancer,medullary thyroid cancer and anaplastic thyroid cancer; pancreaticcancer such as but not limited to, insulinoma, gastrinoma, glucagonoma,vipoma, somatostatin-secreting tumor, and carcinoid or islet cell tumor;pituitary cancers such as but limited to Cushing's disease,prolactin-secreting tumor, acromegaly, and diabetes insipius; eyecancers such as but not limited to ocular melanoma such as irismelanoma, choroidal melanoma, and cilliary body melanoma, andretinoblastoma; vaginal cancers such as squamous cell carcinoma,adenocarcinoma, and

melanoma; vulvar cancer such as squamous cell carcinoma, melanoma,adenocarcinoma, basal cell carcinoma, sarcoma, and Paget's disease;cervical cancers such as but not limited to, squamous cell carcinoma,and adenocarcinoma; uterine cancers such as but not limited toendometrial carcinoma and uterine sarcoma; ovarian cancers such as butnot limited to, ovarian epithelial carcinoma, borderline tumor, germcell tumor, and stromal tumor; esophageal cancers such as but notlimited to, squamous cancer, adenocarcinoma, adenoid cyctic carcinoma,mucoepidermoid carcinoma, adenosquamous carcinoma, sarcoma, melanoma,plasmacytoma, verrucous carcinoma, and oat cell (small cell) carcinoma;stomach cancers such as but not limited to, adenocarcinoma, fungating(polypoid), ulcerating, superficial spreading, diffusely spreading,malignant lymphoma, liposarcoma, fibrosarcoma, and carcinosarcoma; coloncancers; rectal cancers; liver cancers such as but not limited tohepatocellular carcinoma and hepatoblastoma, gallbladder cancers such asadenocarcinoma; cholangiocarcinomas such as but not limited topappillary, nodular, and diffuse; lung cancers such as non-small celllung cancer, squamous cell carcinoma (epidermoid carcinoma),adenocarcinoma, large-cell carcinoma and small-cell lung cancer;testicular cancers such as but not limited to germinal tumor, seminoma,anaplastic, classic (typical), spermatocytic, nonseminoma, embryonalcarcinoma, teratoma carcinoma, choriocarcinoma (yolk-sac tumor),prostate cancers such as but not limited to, adenocarcinoma,leiomyosarcoma, and rhabdomyosarcoma; penal cancers; oral cancers suchas but not limited to squamous cell carcinoma; basal cancers; salivarygland cancers such as but not limited to adenocarcinoma, mucoepidermoidcarcinoma, and adenoidcystic carcinoma; pharynx cancers such as but notlimited to squamous cell cancer, and verrucous; skin cancers such as butnot limited to, basal cell carcinoma, squamous cell carcinoma andmelanoma, superficial spreading melanoma, nodular melanoma, lentigomalignant melanoma, acral lentiginous melanoma; kidney cancers such asbut not limited to renal cell cancer, adenocarcinoma, hypernephroma,fibrosarcoma, transitional cell cancer (renal pelvis and/or uterer);Wilms' tumor; bladder cancers such as but not limited to transitionalcell carcinoma, squamous cell cancer, adenocarcinoma, carcinosarcoma. Inaddition, cancers include myxosarcoma, osteogenic sarcoma,endotheliosarcoma, lymphangioendotheliosarcoma, mesothelioma, synovioma,hemangioblastoma, epithelial carcinoma, cystadenocarcinoma, bronchogeniccarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillarycarcinoma and papillary adenocarcinomas (for a review of such disorders,see Fishman et al., 1985, Medicine, 2d Ed., J. B. Lippincott Co.,Philadelphia and Murphy et al., 1997, Informed Decisions. The CompleteBook of Cancer Diagnosis, Treatment, and Recovery, Viking Penguin,Penguin Books U.S.A., Inc., United States of America)

Accordingly, the methods and compositions of the invention are alsouseful in the treatment or prevention of a variety of cancers or otherabnormal proliferative diseases, including (but not limited to) thefollowing: carcinoma, including that of the bladder, breast, colon,kidney, liver, lung, ovary, pancreas, stomach, cervix, thyroid and skin;including squamous cell carcinoma; hematopoietic tumors of lymphoidlineage, including leukemia, acute lymphocytic leukemia, acutelymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Berkettslymphoma; hematopoietic tumors of myeloid lineage, including acute andchronic myelogenous leukemias and promyelocytic leukemia; tumors ofmesenchymal orignin, including fibrosarcoma and rhabdomyoscarcoma; othertumors, including melanoma, seminoma, tetratocarcinoma, neuroblastomaand glioma; tumors of the central and peripheral nervous system,including astrocytoma, glioblastoma multiforme, neuroblastoma, glioma,and schwannomas; solid and blood born tumors; tumors of mesenchymalorigin, including fibrosafcoma, rhabdomyoscarama, and osteosarcoma; andother tumors, including melanoma, xenoderna pegmentosum,keratoactanthoma, seminoma, thyroid follicular cancer andteratocarcinoma. It is also contemplated that cancers caused byaberrations in apoptosis would also be treated by the methods andcompositions of the invention. Such cancers may include but not belimited to follicular lymphomas, carcinomas with p53 mutations, hormonedependent tumors of the breast, prostate and ovary, and precancerouslesions such as familial adenomatous polyposis, and myelodysplasticsyndromes. In specific embodiments, malignancy or dysproliferativechanges (such as metaplasias and dysplasias), or hyperproliferativedisorders, are treated or prevented in the ovary, bladder, breast,colon, lung, skin, pancreas, or uterus. In other specific embodiments,sarcoma, melanoma, or leukemia is treated or prevented.

In preferred embodiments, the methods and compositions of the inventionare used for the treatment and/or prevention of breast, colon, ovarian,lung, and prostate cancers and melanoma and are provided below byexample rather than by limitation.

4.1.2 Other Prophylactic/Therapeutic Agents

According to the invention, therapy by administration of a JNK inhibitoris combined with the administration of one or more therapies such as,but not limited to, chemotherapies, radiation therapies, hormonaltherapies, bone marrow transplants, stem cell replacement therapiesand/or biological therapies/immunotherapies.

In a specific embodiment, the methods of the invention encompass theadministration of one or more angiogenesis inhibitors such as but notlimited to: Angiostatin (plasminogen fragment); antiangiogenicantithrombin III; Angiozyme; ABT-627; Bay 12-9566; Benefin; Bevacizumab;BMS-275291; cartilage-derived inhibitor (CDI); CAI; CD59 complementfragment; CEP-7055; Col 3; Combretastatin A-4; Endostatin (collagenXVIII fragment); Fibronectin fragment; Gro-beta; Halofuginone;Heparinases; Heparin hexasaccharide fragment; HMV833; Human chorionicgonadotropin (hCG); IM-862; Interferon alpha/beta/gamma; Interferoninducible protein (IP-10); Interleukin-12; Kringle 5 (plasminogenfragment); Marimastat; antiinflammatory steroids such as but not limitedto dexamethasone; Metalloproteinase inhibitors (TIMPs);2-Methoxyestradiol; MMI 270 (CGS 27023A); MoAb IMC-ICI 1; Neovastat;NM-3; Panzem; PI-88; Placental ribonuclease inhibitor; Plasminogenactivator inhibitor; Platelet factor-4 (PF4); Prinomastat; Prolactin16kD fragment; Proliferin-related protein (PRP); PTK 787/ZK 222594;Retinoids; Solimastat; Squalamine; SS 3304; SU 5416; SU6668; SU11248;Tetrahydrocortisol-S; tetrathiomolybdate; thalidomide; Thrombospondin-1(TSP-1); TNP-470; Transforming growth factor-beta (TGF-b);Vasculostatin; Vasostatin (calreticulin fragment); ZD6126; ZD 6474;farnesyl transferase inhibitors (FTI); and bisphosphonates.

Additional examples of anti-cancer agents that can be used in thevarious embodiments of the invention, including pharmaceuticalcompositions and dosage forms and kits of the invention, include, butare not limited to: acivicin; aclarubicin; acodazole hydrochloride;acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantroneacetate; aminoglutethimide; amsacrine; anastrozole; anthramycin;asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat;benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate;bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan;cactinomycin; calusterone; caracemide; carbetimer; carboplatin;carmustine; carubicin hydrochloride; carzelesin; cedefingol;chlorambucil; cirolemycin; cisplatin; cladribine; crisnatol mesylate;cyclophosphamide; cytarabine; dacarbazine; dactinomycin; daunorubicinhydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguaninemesylate; diaziquone; docetaxel; doxorubicin; doxorubicin hydrochloride;droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin;edatrexate; eflomithine hydrochloride; elsamitrucin; enloplatin;enpromate; epipropidine; epirubicin hydrochloride; erbulozole; Erbitux™;esorubicin hydrochloride; estramustine; estramustine phosphate sodium;etanidazole; etoposide; etoposide phosphate; etoprine; fadrozolehydrochloride; fazarabine; fenretinide; floxuridine; fludarabinephosphate; fluorouracil; flurocitabine; fosquidone; fostriecin sodium;gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicinhydrochloride; ifosfamide; ilmofosine; ImiDs™; interleukin II (includingrecombinant interleukin II, or rIL2), interferon-2a; interferonalpha-2b; interferon alpha-n1; interferon alpha-n3; interferon beta-I a;interferon gamma-I b; iproplatin; irinotecan hydrochloride; lanreotideacetate; letrozole; leuprolide acetate; liarozole hydrochloride;lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol;maytansine; mechlorethamine hydrochloride; megestrol acetate;melengestrol acetate; melphalan; menogaril; mercaptopurine;methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide;mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper;mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole;nogalamycin; onnaplatin; oxisuran; paclitaxel; pegaspargase; peliomycin;pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan;piroxantrone hydrochloride; plicamycin; plomestane; porfimer sodium;porfiromycin; prednimustine; procarbazine hydrochloride; puromycin;puromycin hydrochloride; pyrazofurin; riboprine; rogletimide; safingol;safingol hydrochloride; SelCid™; semustine; simtrazene; sparfosatesodium; sparsomycin; spirogermanium hydrochloride; spiromustine;spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin;tecogalan sodium; tegafur; teloxantrone hydrochloride; temoporfin;teniposide; teroxirone; testolactone; thiamiprine; thioguanine;temozolomide; temodar; thiotepa; tiazofurin; tirapazamine; toremifenecitrate; trestolone acetate; triciribine phosphate; trimetrexate;trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracilmustard; uredepa; vapreotide; verteporfin; vinblastine sulfate;vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate;vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate;vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin;zinostatin; zorubicin hydrochloride. Other anti-cancer drugs include,but are not limited to: 20-epi-1,25 dihydroxyvitamin D3;5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol;adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine;amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine;anagrelide; anastrozole; andrographolide; angiogenesis inhibitors;antagonist D; antagonist G; antarelix; anti-dorsalizing morphogeneticprotein-1; antiandrogen, prostatic carcinoma; antiestrogen;antineoplaston; aphidicolin glycinate; apoptosis gene modulators;apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; argininedeaminase; asulacrine; atamestane; atrimustine; axinastatin 1;axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatinIII derivatives; balanol; batimastat; BCR/ABL antagonists;benzochlorins; benzoylstaurosporine; beta lactam derivatives;beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor;bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistrateneA; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine;calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2;capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRestM3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinaseinhibitors (ICOS); cell-cycle inhibitors (e.g., flavopiridol A,tryprostatin B, p19ink4D); cyclin-dependent kinase inhibitors (e.g.,roscovitine, olomucine and purine analogs); MAP kinase inhibitors(CNI-1493); castanospermine; cecropin B; cetrorelix; chlorlns;chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine;clomifene analogues; clotrimazole; collismycin A; collismycin B;combretastatin A4; combretastatin analogue; conagenin; crambescidin 816;crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A;cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate;cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B;deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil;diaziquone; didemnin B; didox; diethylnorspermine;dihydro-5-azacytidine; dihydrotaxol, 9-; dioxamycin; diphenylspiromustine; docetaxel; docosanol; dolasetron; doxifluridine;droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine;edelfosine; edrecolomab; eflornithine; elemene; emitefur; epirubicin;epristeride; estramustine analogue; estrogen agonists; estrogenantagonists; etanidazole; etoposide phosphate; exemestane; fadrozole;fazarabine; fenretinide; filgrastim; finasteride; flavopiridol;flezelastine; fluasterone; fludarabine; fluorodaunorunicinhydrochloride; forfenimex; formestane; fostriecin; fotemustine;gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix;gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam;heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid;idarubicin; idoxifene; idramantone; ilmofosine; ilomastat;imidazoacridones; imiquimod; immunostimulant peptides; insulin-likegrowth factor-1 receptor inhibitor; interferon agonists; interferons;interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact;irsogladine; isobengazole; isohomohalicondrin B; itasetron;jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide;leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole;leukemia inhibiting factor; leukocyte alpha interferon;leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole;linear polyamine analogue; lipophilic disaccharide peptide; lipophilicplatinum compounds; lissoclinamide 7; lobaplatin; lombricine;lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine;lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides;maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysininhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone;meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone;miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone;mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growthfactor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonalantibody, human chorionic gonadotrophin; monophosphoryl lipidA+myobacterium cell wall sk; mopidamol; multiple drug resistance geneinhibitor; multiple tumor suppressor 1-based therapy; mustard anticanceragent; mycaperoxide B; mycobacterial cell wall extract; myriaporone;N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip;naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin;nemorubicin; neridronic acid; neutral endopeptidase; nilutamide;nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn;O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone;ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin;osaterone; oxaliplatin; oxaunomycin; paclitaxel; paclitaxel analogues;paclitaxel derivatives; palauamine; palmitoylrhizoxin; pamidronic acid;panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase;peldesine; pentosan polysulfate sodium; pentostatin; pentrozole;perflubron; perfosfamide; perillyl alcohol; phenazinomycin;phenylacetate; phosphatase inhibitors; picibanil; pilocarpinehydrochloride; pirarubicin; piritrexim; placetin A; placetin B;plasminogen activator inhibitor; platinum complex; platinum compounds;platinum-triamine complex; porfimer sodium; porfiromycin; prednisone;propyl bis-acridone; prostaglandin J2; proteasome inhibitors; proteinA-based immune modulator; protein kinase C inhibitor; protein kinase Cinhibitors, microalgal; protein tyrosine phosphatase inhibitors; purinenucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine;pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists;raltitrexed; ramosetron; retinoic acid (e.g., 9-cis RA); histonedeacetylase inhibitors (e.g., sodium butyrate, suberoylanilidehydroxamic acid); TRAIL; ras farnesyl protein transferase inhibitors;ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide;rohitukine; romurtide; roquinimex; rubiginone B1; ruboxyl; safingol;saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics;semustine; senescence derived inhibitor 1; sense oligonucleotides;signal transduction inhibitors; signal transduction modulators; singlechain antigen binding protein; sizofiran; sobuzoxane; sodiumborocaptate; sodium phenylacetate; solverol; somatomedin bindingprotein; sonermin; sparfosic acid; spicamycin D; spiromustine;splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-celldivision inhibitors; stipiamide; stromelysin inhibitors; sulfinosine;superactive vasoactive intestinal peptide antagonist; suradista;suramin; swainsonine; synthetic glycosaminoglycans; tallimustine;tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium;tegafur; tellurapyrylium; telomerase inhibitors; temoporfin;temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine;thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic;thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroidstimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocenebichloride; topsentin; toremifene; totipotent stem cell factor;translation inhibitors; tretinoin; triacetyluridine; triciribine;trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinaseinhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenitalsinus-derived growth inhibitory factor; urokinase receptor antagonists;vapreotide; variolin B; vector system, erythrocyte gene therapy;velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine;vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatinstimalamer. Preferred additional anti-cancer drugs are 5-fluorouraciland leucovorin. These two agents are particularly useful when used inmethods employing thalidomide and a topoisomerase inhibitor.

In more particular embodiments, the present invention also comprises theadministration of one or more inhibitors of JNK in combination with theadministration of one or more therapies such as, but not limited toagents such as those disclosed in Table I, preferably for the treatmentof breast, ovary, prostate, colon and lung cancers as described above.TABLE 1 Therapeutic Agent Dose/Administration/Formulation doxorubicinIntravenous 60-75 mg/m² on Day 1 21 day intervals hydrochloride(Adriamycin RDF ® and Adriamycin PFS ®) epirubicin Intravenous 100-120mg/m² on Day 1 of each 3-4 week cycles hydrochloride cycle or(Ellence ™) divided equally and given on Days 1-8 of the cyclefluorouracil Intravenous How supplied: as needed or prescribed 5 mL and10 mL vials (containing 250 and 500 mg flourouracil respectively)docetaxel Intravenous 60-100 mg/m² over 1 hour Once every 3 weeks(Taxotere ®) paclitaxel Intravenous 175 mg/m² over 3 hours Every 3 weeksfor (Taxol ®) 4 courses (administered sequentially to doxorubicin-containing combination chemotherapy) tamoxifen citrate Oral 20-40 mgDaily (Nolvadex ®) (tablet) Dosages greater than 20 mg should be givenin divided doses (morning and evening) leucovorin calcium Intravenous orHow supplied: Dosage is unclear from text. for injection intramuscular350 mg vial PDR 3610 injection luprolide acetate Single 1 mg (0.2 mL or20 unit mark) Once a day (Lupron ®) subcutaneous injection flutamideOral (capsule) 250 mg 3 times a day at 8 hour (Eulexin ®) (capsulescontain 125 mg intervals (total daily dosage flutamide each) 750 mg)nilutamide Oral 300 mg or 150 mg 300 mg once a day for 30 days(Nilandron ®) (tablet) (tablets contain 50 or 150 mg followed by 150 mgonce a nilutamide each) day bicalutamide Oral 50 mg Once a day(Casodex ®) (tablet) (tablets contain 50 mg bicalutamide each)progesterone Injection USP in sesame oil 50 mg/mL as needed orprescribed ketoconazole Cream 2% cream applied once or twice as neededor prescribed (Nizoral ®) daily depending on symptoms prednisone OralInitial dosage may vary from 5 as needed or prescribed (tablet) mg to 60mg per day depending on the specific disease entity being treated.estramustine Oral 14 mg/kg of body weight (i.e. Daily given in 3 or 4divided phosphate sodium (capsule) one 140 mg capsule for each 10 doses(Emcyt ®) kg or 22 lb of body weight) etoposide or Intravenous 5 mL of20 mg/mL solution as needed or prescribed VP-16 (100 mg) dacarbazineIntravenous 2-4.5 mg/kg Once a day for 10 days. (DTIC-Dome ®) May berepeated at 4 week intervals polifeprosan 20 wafer placed 8 wafers, eachcontaining 7.7 mg as needed or prescribed with carmustine in resectionof carmustine, for a total of 61.6 implant (BCNU) cavity mg, if size andshape of resection (nitrosourea) cavity allows (Gliadel ®) cisplatinInjection [n/a in PDR 861] as needed or prescribed How supplied:solution of 1 mg/mL in multi- dose vials of 50 mL and 100 mL mitomycinInjection supplied in 5 mg and 20 mg vials as needed or prescribed(containing 5 mg and 20 mg mitomycin) gemcitabine HCl Intravenous ForNSCLC-2 schedules have 4 week schedule- (Gemzar ®) been investigated andthe Days 1, 8 and 15 of each 28- optimum schedule has not been daycycle. Cisplatin determined intravenously at 100 mg/m² on 4 weekschedule- day 1 after the infusion of administration intravenously atGemzar. 1000 mg/m² over 30 minutes on 3 week schedule- 3 week schedule-Days 1 and 8 of each 21 day Gemzar administered cycle. Cisplatin atdosage of intravenously at 1250 mg/m² 100 mg/m² administered over 30minutes intravenously after administration of Gemzar on day 1.carboplatin Intravenous Single agent therapy: Every 4 weeks(Paraplatin ®) 360 mg/m² I.V. on day 1 (infusion lasting 15 minutes orlonger) Other dosage calculations: Combination therapy withcyclophosphamide, Dose adjustment recommendations, Formula dosing, etc.ifosamide Intravenous 1.2 g/m² daily 5 consecutive days (Ifex ®) Repeatevery 3 weeks or after recovery from hematologic toxicity topotecanIntravenous 1.5 mg/m² by intravenous 5 consecutive days, starting onhydrochloride infusion over 30 minutes daily day 1 of 21 day course(Hycamtin ®) cyclophosphamide Parenteral or 1-5 mg/kg/day as needed orprescribed Oral irinotecan Intraveinous or 20-500 mg/m² as needed orprescribed Infusion

The invention also encompasses administration of JNK inhibitors incombination with radiation therapy comprising the use of x-rays, gammarays and other sources of radiation to destroy the cancer cells. Inpreferred embodiments, the radiation treatment is administered asexternal beam radiation or teletherapy wherein the radiation is directedfrom a remote source. In other preferred embodiments, the radiationtreatment is administered as internal therapy or brachytherapy wherein aradiaoactive source is placed inside the body close to cancer cells or atumor mass.

4.2 Pharmaceutical Compositions

The compositions of the invention include bulk drug compositions usefulin the manufacture of pharmaceutical compositions (e.g., impure ornon-sterile compositions) and pharmaceutical compositions (i.e.,compositions that are suitable for administration to a patient) whichcan be used in the preparation of unit dosage forms. Such compositionscomprise a prophylactically or therapeutically effective amount of aprophylactic and/or therapeutic agent disclosed herein or a combinationof those agents and a pharmaceutically acceptable carrier. Preferably,compositions of the invention comprise a prophylactically ortherapeutically effective amount of JNK inhibitor and/or an anti-canceragent, and a pharmaceutically acceptable carrier.

In a specific embodiment, the term “pharmaceutically acceptable” meansapproved by a regulatory agency of the Federal or a state government orlisted in the U.S. Pharmacopeia or other generally recognizedpharmacopeia for use in animals, and more particularly in humans. Theterm “carrier” refers to a diluent, adjuvant, excipient, or vehicle withwhich a compound of the invention is administered. Such pharmaceuticalvehicles can be liquids, such as water and oils, including those ofpetroleum, animal, vegetable or synthetic origin, such as peanut oil,soybean oil, mineral oil, sesame oil and the like. The pharmaceuticalvehicles can be saline, gum acacia, gelatin, starch paste, talc,keratin, colloidal silica, urea, and the like. In addition, auxiliary,stabilizing, thickening, lubricating and coloring agents may be used.When administered to a patient, the compounds of the invention andpharmaceutically acceptable vehicles are preferably sterile. Water is apreferred vehicle when the compound of the invention is administeredintravenously. Saline solutions and aqueous dextrose and glycerolsolutions can also be employed as liquid vehicles, particularly forinjectable solutions. Suitable pharmaceutical vehicles also includeexcipients such as starch, glucose, lactose, sucrose, gelatin, malt,rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate,talc, sodium chloride, dried skim milk, glycerol, propyleneglycol,water, ethanol and the like. The present compositions, if desired, canalso contain minor amounts of wetting or emulsifying agents, or pHbuffering agents.

The present compositions can take the form of solutions, suspensions,emulsion, tablets, pills, pellets, capsules, capsules containingliquids, powders, sustained-release formulations, suppositories,emulsions, aerosols, sprays, suspensions, or any other form suitable foruse. In one embodiment, the pharmaceutically acceptable vehicle is acapsule (see e.g., U.S. Pat. No. 5,698,155). Other examples of suitablepharmaceutical vehicles are described in “Remington's PharmaceuticalSciences” by E. W. Martin.

In a preferred embodiment, the compounds of the invention are formulatedin accordance with routine procedures as a pharmaceutical compositionadapted for intravenous administration to human beings. Typically,compounds of the invention for intravenous administration are solutionsin sterile isotonic aqueous buffer. Where necessary, the compositionsmay also include a solubilizing agent. Compositions for intravenousadministration may optionally include a local anesthetic such aslignocaine to ease pain at the site of the injection. Generally, theingredients are supplied either separately or mixed together in unitdosage form, for example, as a dry lyophilized powder or water freeconcentrate in a hermetically sealed container such as an ampoule orsachette indicating the quantity of active agent. Where the compound ofthe invention is to be administered by infusion, it can be dispensed,for example, with an infusion bottle containing sterile pharmaceuticalgrade water or saline. Where the compound of the invention isadministered by injection, an ampoule of sterile water for injection orsaline can be provided so that the ingredients may be mixed prior toadministration.

Compositions for oral delivery may be in the form of tablets, lozenges,aqueous or oily suspensions, granules, powders, emulsions, capsules,syrups, or elixirs, for example. Orally administered compositions maycontain one or more optional agents, for example, sweetening agents suchas fructose, aspartame or saccharin; flavoring agents such aspeppermint, oil of wintergreen, or cherry; coloring agents; andpreserving agents, to provide a pharmaceutically palatable preparation.Moreover, where in tablet or pill form, the compositions may be coatedto delay disintegration and absorption in the gastrointestinal tractthereby providing a sustained action over an extended period of time.Selectively permeable membranes surrounding an osmotically activedriving compound are also suitable for orally administered compounds ofthe invention. In these later platforms, fluid from the environmentsurrounding the capsule is imbibed by the driving compound, which swellsto displace the agent or agent composition through an aperture. Thesedelivery platforms can provide an essentially zero order deliveryprofile as opposed to the spiked profiles of immediate releaseformulations. A time delay material such as glycerol monostearate orglycerol stearate may also be used. Oral compositions can includestandard vehicles such as mannitol, lactose, starch, magnesium stearate,sodium saccharine, cellulose, magnesium carbonate, etc. Such vehiclesare preferably of pharmaceutical grade.

Further, the effect of the compounds of this invention may be delayed orprolonged by proper formulation. For example, a slowly soluble pellet ofthe compound may be prepared and incorporated in a tablet or capsule.The technique may be improved by making pellets of several differentdissolution rates and filling capsules with a mixture of the pellets.Tablets or capsules may be coated with a film which resists dissolutionfor a predictable period of time. Even the parenteral preparations maybe made long-acting, by dissolving or suspending the compound in oily oremulsified vehicles which allow it to disperse only slowly in the serum.

4.2.1 Formulations

Pharmaceutical compositions for use in accordance with the presentinvention may be formulated in conventional manner using one or morephysiologically acceptable carriers or excipients.

Thus, the JNK inhibitors or other anti-cancer agents and theirphysiologically acceptable salts and solvates may be formulated foradministration by inhalation or insufflation (either through the mouthor the nose) or oral, parenteral or mucosol (such as buccal, vaginal,rectal, sublingual) administration. In a preferred embodiment, local orsystemic parenteral administration is used.

For oral administration, the pharmaceutical compositions may take theform of, for example, tablets or capsules prepared by conventional meanswith pharmaceutically acceptable excipients such as binding agents(e.g., pregelatinised maize starch, polyvinylpyrrolidone orhydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystallinecellulose or calcium hydrogen phosphate); lubricants (e.g., magnesiumstearate, talc or silica); disintegrants (e.g., potato starch or sodiumstarch glycolate); or wetting agents (e.g., sodium lauryl sulphate). Thetablets may be coated by methods well known in the art. Liquidpreparations for oral administration may take the form of, for example,solutions, syrups or suspensions, or they may be presented as a dryproduct for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may be prepared by conventional means withpharmaceutically acceptable additives such as suspending agents (e.g.,sorbitol syrup, cellulose derivatives or hydrogenated edible fats);emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles(e.g., almond oil, oily esters, ethyl alcohol or fractionated vegetableoils); and preservatives (e.g., methyl or propyl-p-hydroxybenzoates orsorbic acid). The preparations may also contain buffer salts, flavoring,coloring and sweetening agents as appropriate.

Preparations for oral administration may be suitably formulated to givecontrolled release of the active compound.

For buccal administration the compositions may take the form of tabletsor lozenges formulated in conventional manner.

For administration by inhalation, the prophylactic or therapeutic agentsfor use according to the present invention are conveniently delivered inthe form of an aerosol spray presentation from pressurized packs or anebuliser, with the use of a suitable propellant, e.g.,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol the dosage unit may be determined byproviding a valve to deliver a metered amount. Capsules and cartridgesof e.g., gelatin for use in an inhaler or insufflator may be formulatedcontaining a powder mix of the compound and a suitable powder base suchas lactose or starch.

The prophylactic or therapeutic agents may be formulated for parenteraladministration by injection, e.g., by bolus injection or continuousinfusion. Formulations for injection may be presented in unit dosageform, e.g., in ampoules or in multi-dose containers, with an addedpreservative. The compositions may take such forms as suspensions,solutions or emulsions in oily or aqueous vehicles, and may containformulatory agents such as suspending, stabilizing and/or dispersingagents. Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g., sterile pyrogen-free water,before use.

The prophylactic or therapeutic agents may also be formulated in rectalcompositions such as suppositories or retention enemas, e.g., containingconventional suppository bases such as cocoa butter or other glycerides.

In addition to the formulations described previously, the prophylacticor therapeutic agents may also be formulated as a depot preparation.Such long acting formulations may be administered by implantation (forexample subcutaneously or intramuscularly) or by intramuscularinjection. Thus, for example, the prophylactic or therapeutic agents maybe formulated with suitable polymeric or hydrophobic materials (forexample as an emulsion in an acceptable oil) or ion exchange resins, oras sparingly soluble derivatives, for example, as a sparingly solublesalt.

The invention also provides that a prophylactic or therapeutic agent ispackaged in a hermetically sealed container such as an ampoule orsachette indicating the quantity. In one embodiment, the prophylactic ortherapeutic agent is supplied as a dry sterilized lyophilized powder orwater free concentrate in a hermetically sealed container and can bereconstituted, e.g., with water or saline to the appropriateconcentration for administration to a patient.

In a preferred embodiment of the invention, the formulation andadministration of various chemotherapeutic, biological/immunotherapeuticand hormonal therapeutic agents are known in the art and often describedin the Physician's Desk Reference, 56^(th) ed. (2002). For instance, incertain specific embodiments of the invention, the therapeutic agents ofthe invention can be formulated and supplied as provided in Table 1.

In other embodiments of the invention, radiation therapy agents such asradioactive isotopes can be given orally as liquids in capsules or as adrink. Radioactive isotopes can also be formulated for intravenousinjections. The skilled oncologist can determine the preferredformulation and route of administration.

The compositions may, if desired, be presented in a pack or dispenserdevice that may contain one or more unit dosage forms containing theactive ingredient. The pack may for example comprise metal or plasticfoil, such as a blister pack. The pack or dispenser device may beaccompanied by instructions for administration.

In certain preferred embodiments, the pack or dispenser contains one ormore unit dosage forms containing no more than 5 mg/mL of a JNKinhibitor and no more than the recommended dosage formulation asdetermined in the Physician's Desk Reference (56^(th) ed. 2002, hereinincorporated by reference in its entirety) for a particular cancertherapy.

4.3 Routes of Administration

Methods of administering a prophylactic or therapeutic agent of theinvention include, but are not limited to, parenteral administration(e.g., intradermal, intramuscular, intraperitoneal, intravenous andsubcutaneous), epidural, and mucosal (e.g., intranasal, rectal, vaginal,sublingual, buccal or oral routes). In a specific embodiment,prophylactic or therapeutic agents of the invention are administeredintramuscularly, intravenously, or subcutaneously. The prophylactic ortherapeutic agents may also be administered by infusion or bolusinjection and may be administered together with other biologicallyactive agents. Administration can be local or systemic. The JNKinhibitors or other biologically active agents and their physiologicallyacceptable salts and solvates may also be administered by inhalation orinsufflation (either through the mouth or the nose). In a preferredembodiment, local or systemic parenteral administration is used.

In specific embodiments, it may be desirable to administer one or morecompounds of the invention locally to the area in need of treatment.This may be achieved, for example, and not by way of limitation, bylocal infusion during surgery, topical application, e.g., in conjunctionwith a wound dressing after surgery, by injection, by means of acatheter, by means of a suppository, or by means of an implant, saidimplant being of a porous, non-porous, or gelatinous material, includingmembranes, such as sialastic membranes, or fibers. In one embodiment,administration can be by direct injection at the site (or former site)of an atherosclerotic plaque tissue.

Pulmonary administration can also be employed, e.g., by use of aninhaler or nebulizer, and formulation with an aerosolizing agent, or viaperfusion in a fluorocarbon or synthetic pulmonary surfactant. Incertain embodiments, the compounds of the invention can be formulated asa suppository, with traditional binders and vehicles such astriglycerides.

In another embodiment, the compounds of the invention can be deliveredin a vesicle, in particular a liposome (see Langer, 1990, Science249:1527-1533; Treat et al., in Liposomes in the Therapy of InfectiousDisease and Cancer, Lopez-Berestein and Fidler (eds.), Liss, New York,pp. 353-365 (1989); Lopez-Berestein, ibid., pp. 317-327; see generallyibid.).

In yet another embodiment, the compounds of the invention can bedelivered in a controlled release system. In one embodiment, a pump maybe used (see Langer, supra; Sefton, 1987, CRC Crit. Ref. Biomed. Eng.14:201; Buchwald et al., 1980, Surgery 88:507 Saudek et al., 1989, N.Engl. J. Med. 321:574). In another embodiment, polymeric materials canbe used (see Medical Applications of Controlled Release, Langer and Wise(eds.), CRC Pres., Boca Raton, Fla. (1974); Controlled DrugBioavailability, Drug Product Design and Performance, Smolen and Ball(eds.), Wiley, New York (1984); Ranger and Peppas, 1983, J. Macromol.Sci. Rev. Macromol. Chem. 23:61; see also Levy et al., 1985, Science228:190; During et al., 1989, Ann. Neurol. 25:351; Howard et al., 1989,J. Neurosurg. 71:105). In yet another embodiment, a controlled-releasesystem can be placed in proximity of the target of the compounds of theinvention, e.g., the liver, thus requiring only a fraction of thesystemic dose (see, e.g., Goodson, in Medical Applications of ControlledRelease, supra, vol. 2, pp. 115-138 (1984)). Other controlled-releasesystems discussed in the review by Langer, 1990, Science 249:1527-1533)may be used.

4.4 Dosages

The amount of the composition of the invention which will be effectivein the treatment, prevention or management of cancer can be determinedby standard research techniques. For example, the dosage of thecomposition which will be effective in the treatment, prevention ormanagement of cancer can be determined by administering the compositionto an animal model such as, e.g., the animal models disclosed herein orknown to those skilled in the art. In addition, in vitro assays mayoptionally be employed to help identify optimal dosage ranges.

Selection of the preferred effective dose can be determined (e.g., viaclinical trials) by a skilled artisan based upon the consideration ofseveral factors which will be known to one of ordinary skill in the art.Such factors include the disease to be treated or prevented, thesymptoms involved, the patient's body mass, the patient's immune statusand other factors known by the skilled artisan to reflect the accuracyof administered pharmaceutical compositions.

The precise dose to be employed in the formulation will also depend onthe route of administration, and the seriousness of the cancer, andshould be decided according to the judgment of the practitioner and eachpatient's circumstances. Effective doses may be extrapolated fromdose-response curves derived from in vitro or animal model test systems.

The general range of effective administration rates of the compounds ofthis invention are from about 0.001 mg/day to about 3000 mg/day, morepreferably from about 0.001 mg/day to 2500 mg/day, more preferably fromabout 0.001 mg/day to 1500 mg/day, more preferably from about 0.001mg/day to 750 mg/day, more preferably from about 0.001 mg/day to 250mg/day, more preferably from about 0.001 mg/day to 75 mg/day, morepreferably from about 0.001 mg/day to 50 mg/day, more preferably fromabout 0.001 mg/day to 25 mg/day, more preferably from about 0.001 mg/dayto 10 mg/day, more preferably from about 0.001 mg/day to 1 mg/day. Ofcourse, it is often practical to administer the daily dose of compoundin portions, at various hours of the day. However, in any given case,the amount of compound administered will depend on such factors as thesolubility of the active component, the formulation used, subjectcondition (such as weight), and/or the route of administration.

For antibodies, the dosage administered to a patient is typically 0.1mg/kg to 100 mg/kg of the patient's body weight. Preferably, the dosageadministered to a patient is between 0.1 mg/kg and 20 mg/kg of thepatient's body weight, more preferably 1 mg/kg to 10 mg/kg of thepatient's body weight. Generally, human and humanized antibodies have alonger half-life within the human body than antibodies from otherspecies due to the immune response to the foreign polypeptides. Thus,lower dosages of human antibodies and less frequent administration isoften possible.

For other cancer therapeutic agents administered to a patient, thetypical doses of various cancer therapeutics known in the art areprovided in Table 1. Given the invention, certain preferred embodimentswill encompass the administration of lower dosages in combinationtreatment regimens than dosages recommended for the administration ofsingle agents.

Cancer therapies and their dosages, routes of administration andrecommended usage are known in the art and have been described in suchliterature as the Physician's Desk Reference (56^(th) ed., 2002).

The invention provides for any method of administrating lower doses ofknown prophylactic or therapeutic agents than previously thought to beeffective for the prevention, treatment, management or amelioration ofcancer. Preferably, lower doses of known anti-cancer therapies areadministered in combination with lower doses of JNK inhibitors.

4.5 Kits

The invention provides a pharmaceutical pack or kit comprising one ormore containers filled with JNK inhibitor and one or more otherprophylactic or therapeutic agents useful for the treatment of a cancer.The invention also provides a pharmaceutical pack or kit comprising oneor more containers filled with one or more of the ingredients of thepharmaceutical compositions of the invention. Optionally associated withsuch container(s) can be a notice in the form prescribed by agovernmental agency regulating the manufacture, use or sale ofpharmaceuticals or biological products, which notice reflects approvalby the agency of manufacture, use or sale for human administration.

The present invention provides kits that can be used in the abovemethods. In one embodiment, a kit comprises a JNK inhibitor, in one ormore containers, and one or more other prophylactic or therapeuticagents useful for the treatment of cancer, in one or more containers. Incertain preferred embodiments, the other prophylactic or therapeuticagent is a chemotherapeutic. In certain preferred embodiments, theprophylactic or therapeutic agent is a biological or hormonaltherapeutic. In an alterative embodiment, a kit comprises a JNKinhibitor and one or more other prophylactic or therapeutic agentsuseful for the treatment of cancer, in one or more containers.

5. EXAMPLES

The following examples are offered by way of illustration, notlimitation.

5.1 JNK Inhibitor A and JNK Inhibitor B in Combination Therapy UsingLewis Lung Carcinoma (LLC)

This experiment was performed in vitro to determine the effect on LewisLung Carcinoma (LLC) proliferation of combination treatment with JNKinhibitor A and JNK inhibitor B (JNK inhibitorA=((2H-Dibenzo(cd,g)indazol-6-one)); JNK inhibitorB=(3-(4-fluoro-phenyl)-5-(2H-(1,2,4)triazol-3-yl)-1H-indazole)) andanti-cancer agents. The results are illustrated in FIGS. 1A and 1B.

LLC cells were grown in DMEM with 10% FBS. Cells were subsequentlytreated on the second day with either DMSO,JNK inhibitor A (3 mM, 10 mMor 30 mM), JNK inhibitor B (1 mM, 3 mM, or 10 mM), or a chemodrug (i.e.,doxorubican, 5-fluorouridine (5-FU), cisplatin or paclitaxel)(concentrations ranging from 0.001 mM to 10 mM) or a combination of JNKinhibitor A or JNK inhibitor B with a chemodrug. Cell proliferation wasmeasured at 48 hours after treatment by Alamar Blue fluorescence.

Treatment of cells with a combination of JNK inhibitor A or JNKinhibitor B and a chemodrug resulted in increased killing of cellsrelative to treatment with JNK inhibitor A or JNK inhibitor B or achemodrug alone.

5.2 Combination of JNK inhibitor B and Cyclophosphamide Blocks LewisLung Carcinoma (LLC) Tumor Growth

This experiment was performed to determine if JNK inhibitors willenhance the antitumor effects of cyclophosphamide (CTX) in combinationtreatment. Results are illustrated in FIG. 2.

Lewis Lung Carcinoma (LLC) tumors were injected into C57BL/6 mice (50mice, 10/group), 1×106 cells in 0.1 ml Matrigel. Tumors were treated theday after inoculation by administration of vehicle alone (0.5% CMC/0.25%Tween 80), cyclophosphamide (CTX, 50 mg/kg, ip, q3d), SPC2 (75 mg/kg,ip, b.i.d.) or CTX in combination with JNK inhibitor B. Tumor volume wasrecorded over a period of 17 days. Tumor volume was calculated by theformula: mm3=(L×W2)/2. In the CTX/JNK inhibitor B combination group,7/10 animals had no measurable tumors at the end of the study.

These results demonstrate the additive if not synergistic effect ontumor reduction by combination treatment with a JNK inhibitor andanti-cancer agent.

5.3 JNK Inhibitor A Potentiates Chemotherapeutic Induction of Apootosis

The following experiment was performed to determine the effectiveness ofcombination treatment with JNK inhibitor A and a chemodrug on apoptosis.The results are illustrated in FIG. 3. MiaPaCa cells (100,000/well) wereplated in 6 well plates. Following overnight incubation, vehicle ortaxol was added alone for the first 7 hours, washed out, and then JNKinhibitor A or vehicle were added for the remainder of the experiment.After 48 hours, each sample was trypsinized, stained with DiOC6 andanalyzed by flow cytometry on a Coulter Epics flow cytometer usingFlowJo software.

The results demonstrate the effect on MiaPaCa cell apoptosis bycombination treatment with JNK inhibitor A and taxol as compared totreatment with taxol alone.

5.4 Combination of JNK inhibitor A and Cyclophosphamide Blocks LewisLung Carcinoma (LLC) Tumor Growth

The following experiment was performed to determine the effectiveness ofcombination treatment with JNK inhibitor A and cyclophosphamide. Theresults are illustrated in FIG. 4.

Tumor cells were cultured under normal conditions, harvested withtrypsin, washed with PBS then resuspended, 1×107 cells/ml in Matrigel(Collaborative). C57BL/6 mice (female, 18-20 g, Charles River) werelightly anesthetized using Isofluorane then inoculated, subcutaneously,under the right flank with 0.1 ml Matrigel containing 1×106 tumor cells.Mice were randomized into treatment groups immediately after cellinoculation. After 3 days tumor growth treatment began. Mice wereadministered vehicle alone (DMSO), cyclophosphamide (CTX), JNK inhibitorA or CTX in combination with JNK inhibitor A. Tumor volumes weredetermined by caliper measurement. Tumor volume was calculated by theformula: mm³=(L×W2)/2. Values are mean±sem, N=10. This study demostratesthe antitumor effects of JNK inhibitor A in combination withcyclophosphamide in C57BL/6 mice bearing Lewis lung carcinoma. Tumorinhibition resulting from JNK inhibitor A treatment in combination withcyclophosphamide was significantly less (p=0.05) than that seen withcyclophosphamide alone. This result indicates that JNK inhibitors can beused in combination with cyclophosphamide and other chemotherapeuticdrugs to enhance their efficacy.

5.5 Combination of JNK Inhibitor C and Camptosar Blocks Lewis LungCarcinoma (LLC) Tumor Growth

The following experiment was performed to determine the effectiveness ofcombination treatment with JNK inhibitor C (JNK inhibitorC=(3-(4-(2-Piperidin-1-yl-ethoxy)-cyclohexa-1,5-dienyl)-5-(2H-(1,2,4)triazol-3-yl)-1H-indazole))and Camptosar. The results are illustrated in FIG. 5.

CB17 SCID mice were inoculated subcutaneously with HCT-116 humancolorectal cancer cells. On day 8, mice bearing tumors of 100 mm³ weresegregated into groups and administered i.p. with vehicle (citratebuffer), JNK inhibitor C (15 mg/kg), JNK inhibitor C (30 mg/kg), JNKinhibitor C (15 mg/kg)+Camptosar (1.5 mg/kg), Camptosar (1.5 mg/kg) orCamptosar (10 mg/kg). The tumors were measured twice a week and volumescalculated. The dosing regimen for the compound JNK inhibitor C wasb.i.d and for Camptosar was q4d. The arrows indicate the dosing days ofJNK inhibitor C and Camptosar. The tumor growth in the group treatedwith JNK inhibitor C in combination with Camptosar was significantlyslower than that of either treatments alone. This demonstrates thesynergistic effect of combination therapy with JNK inhibitor C andCamptosar.

1. A method for treating or managing acute myelocytic leukemia in apatient in need thereof, said method comprising administering to saidpatient an effective amount of one or more JNK inhibitors and aneffective amount of cytarabine, wherein the JNK inhibitor is:

wherein: -A-R₁ is phenyl, substituted with —O(CH₂)₂NR₈R₉, and R₈ and R₉taken together with the atom to which they are bonded form aheterocycle; and R₂ is 3-triazolyl; or a pharmaceutically acceptablesalt thereof.
 2. The method of claim 1, wherein the JNK inhibitor is:

or a pharmaceutically acceptable salt thereof.
 3. The method of claim 1,wherein the JNK inhibitor and cytarabine are administered concurrently.4. The method of claim 1, wherein the JNK inhibitor and cytarabine areadministered sequentially.
 5. The method of claim 1, wherein the JNKinhibitor and cytarabine are administered orally, parenterally ormucosally.
 6. The method of claim 5, wherein the JNK inhibitor andcytarabine are administered intravenously.
 7. A method for treating ormanaging acute myelocytic leukemia in a patient in need thereof, saidmethod comprising administering to said patient an effective amount ofone or more JNK inhibitors and an effective amount of daunorubicin,wherein the JNK inhibitor is:

wherein: -A-R₁ is phenyl, substituted with —O(CH₂)₂NR₈R₉, and R₈ and R₉taken together with the atom to which they are bonded form aheterocycle; and R₂ is 3-triazolyl; or a pharmaceutically acceptablesalt thereof.
 8. The method of claim 7, wherein the JNK inhibitor is:

or a pharmaceutically acceptable salt thereof.
 9. The method of claim 7,wherein the JNK inhibitor and daunorubicin are administeredconcurrently.
 10. The method of claim 7, wherein the JNK inhibitor anddaunorubicin are administered sequentially.
 11. The method of claim 7,wherein the JNK inhibitor and daunorubicin are administered orally,parenterally or mucosally.
 12. The method of claim 11, wherein the JNKinhibitor and daunorubicin are administered intravenously.
 13. Apharmaceutical composition comprising a pharmaceutically acceptablecarrier, an effective amount of one or more JNK inhibitors and aneffective amount of cytarabine or daunorubicin, wherein the JNKinhibitor is:

wherein: (a) -A-R₁ is phenyl, substituted with —O(CH₂)₂NR₈R₉, and R₈ andR₉ taken together with the atom to which they are bonded form aheterocycle; and (b) R₂ is 3-triazolyl; or a pharmaceutically acceptablesalt thereof.
 14. The pharmaceutical composition of claim 13, whereinthe JNK inhibitor is:

or a pharmaceutically acceptable salt thereof.
 15. The pharmaceuticalcomposition of claim 13 suitable for oral, parenteral or mucosaladministration.
 16. The pharmaceutical composition of claim 15 suitablefor intravenous administration.
 17. A single unit dosage form comprisingan effective amount of one or more JNK inhibitors and an effectiveamount of cytarabine or daunorubicin, wherein the JNK inhibitor is:

wherein: (a) -A-R₁ is phenyl, substituted with —O(CH₂)₂NR₈R₉, and R₈ andR₉ taken together with the atom to which they are bonded form aheterocycle; and (b) R₂ is 3-triazolyl; or a pharmaceutically acceptablesalt thereof.
 18. The single unit dosage form of claim 17, wherein theJNK inhibitor is:

or a pharmaceutically acceptable salt thereof.
 19. The single unitdosage form of claim 17 suitable for oral, parenteral or mucosaladministration.
 20. The single unit dosage form of claim 19 suitable forintravenous administration.